Pyrazolyl quinoxaline kinase inhibitors

ABSTRACT

The invention relates to new quinoxaline derivative compounds, to pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 13/643,741 (published as US 2013-0072457 A1 on Mar. 21, 2013), whichis a national stage filing under section 371 of InternationalApplication No. PCT/GB2011/050851, filed on Apr. 28, 2011, and publishedin English on Nov. 3, 2011, as WO 2011/135376, and claims priority toBritish Application No. 1007286.6 filed on Apr. 30, 2010, and to U.S.Provisional Application No. 61/329,884, filed on Apr. 30, 2010. Theentire disclosures of each of the prior applications are herebyincorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to new quinoxaline derivative compounds, topharmaceutical compositions comprising said compounds, to processes forthe preparation of said compounds and to the use of said compounds inthe treatment of diseases, e.g. cancer.

SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided compoundsof formula (I):

including any tautomeric or stereochemically isomeric form thereof,wherein

-   n represents an integer equal to 0, 1, 2, 3 or 4;-   R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl, hydroxyC₁₋₆alkyl,    haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl,    C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be    substituted with one or two hydroxyl groups, C₁₋₆alkyl substituted    with —NR⁴R⁵, C₁₋₆alkyl substituted with —C(═O)—NR⁴R⁵,    —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl    substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,    C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl    substituted with —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted    with —NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶,    C₁₋₆alkyl substituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted    with R⁶, C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkyl substituted    with —P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂;-   each R^(1a) is independently selected from hydrogen, C₁₋₄alkyl,    hydroxyC₁₋₄alkyl, C₁₋₄alkyl substituted with amino or mono- or    di(C₁₋₄alkyl)amino or —NH(C₃₋₈cycloalkyl), cyanoC₁₋₄alkyl,    C₁₋₄alkoxyC₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more    fluoro atoms;-   each R² is independently selected from hydroxyl, halogen, cyano,    C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,    hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy,    hydroxyhaloC₁₋₄alkyl, hydroxyhaloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,    haloC₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl    may optionally be substituted with one or two hydroxyl groups,    hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl, R¹³, C₁₋₄alkyl substituted with R¹³,    C₁₋₄alkyl substituted with —C(═O)—R¹³, C₁₋₄alkoxy substituted with    R¹³, C₁₋₄alkoxy substituted with —C(═O)—R¹³, —C(═O)—R¹³, C₁₋₄alkyl    substituted with —NR⁷R⁸, C₁₋₄alkyl substituted with —C(═O)—NR⁷R⁸,    C₁₋₄alkoxy substituted with —NR⁷R⁸, C₁₋₄alkoxy substituted with    —C(═O)—NR⁷R⁸, —NR⁷R⁸ and —C(═O)—NR⁷R⁸; or when two R² groups are    attached to adjacent carbon atoms they may be taken together to form    a radical of formula:    -   —O—(C(R¹⁷)₂)_(p)—O—;    -   —X—CH═CH—; or    -   —X—CH═N—; wherein R¹⁷ represents hydrogen or fluorine, p        represents 1 or 2 and X represents O or S;-   R³ represents hydroxyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxy    substituted with —NR¹⁰R¹¹, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,    haloC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,    hydroxyC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,    hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl, hydroxyhaloC₁₋₆alkyl,    cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with carboxyl, C₁₋₆alkyl    substituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted with    C₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted with    C₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with    —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may    optionally be substituted with one or two hydroxyl groups or with    —O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy,    C₂₋₆alkynyl substituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with    R⁹ and optionally substituted with —O—C(═O)—, C₁₋₆alkyl, C₁₋₆alkyl    substituted with —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and    R⁹, C₂₋₆alkenyl substituted with R⁹, C₂₋₆alkynyl substituted with    R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted    with —NR¹⁰R¹¹, C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl    substituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with    one or two halogens and —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹²,    C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted    with —O—C(═O)—NR¹⁰R¹¹, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl,    —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl,    C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl    substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with    —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with    —NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ or    C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂;-   R⁴ and R⁵ each independently represent hydrogen, C₁₋₆alkyl,    hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,    C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be    substituted with one or two hydroxyl groups, —S(═O)₂—C₁₋₆alkyl,    —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with    —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,    C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted    with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with    —NH—S(═O)₂—NR¹⁴R¹⁵, R¹³ or C₁₋₆alkyl substituted with R¹³;-   R⁶ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to    7-membered monocyclic heterocyclyl containing at least one    heteroatom selected from N, O or S; said C₃₋₈cycloalkyl,    C₃₋₈cycloalkenyl, phenyl, 4 to 7-membered monocyclic heterocyclyl,    optionally and each independently being substituted by 1, 2, 3, 4 or    5 substituents, each substituent independently being selected from    cyano, C₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyl, carboxyl,    hydroxyC₁₋₆alkyl, halogen, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkyl-O—C(═O)—, —NR¹⁴R¹⁵,    —C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkyl    substituted with —C(═O)—NR¹⁴R¹⁵, —S(═O)₂—C₁₋₆alkyl,    —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with    —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,    C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted    with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted with    —NH—S(═O)₂—NR¹⁴R¹⁵;-   R⁷ and R⁸ each independently represent hydrogen, C₁₋₆alkyl,    hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl or    C₁₋₆alkoxyC₁₋₆alkyl;-   R⁹ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, naphthyl, or    3 to 12 membered monocyclic or bicyclic heterocyclyl containing at    least one heteroatom selected from N, O or S, said C₃₋₈cycloalkyl,    C₃₋₈cycloalkenyl, phenyl, naphthyl, or 3 to 12 membered monocyclic    or bicyclic heterocyclyl each optionally and each independently    being substituted with 1, 2, 3, 4 or 5 substituents, each    substituent independently being selected from ═O, C₁₋₄alkyl,    hydroxyl, carboxyl, hydroxyC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl,    C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkyl substituted with C₁₋₄alkyl-O—C(═O)—,    C₁₋₄alkyl-C(═O)—, C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl may    optionally be substituted with one or two hydroxyl groups, halogen,    haloC₁₋₄alkyl, hydroxyhaloC₁₋₄alkyl, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵,    C₁₋₄alkyl substituted with —NR¹⁴R¹⁵, C₁₋₄alkyl substituted with    —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkoxy, —S(═O)₂—C₁₋₄alkyl,    —S(═O)₂-haloC₁₋₄alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with    —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with —NH—S(═O)₂—C₁₋₄alkyl,    C₁₋₄alkyl substituted with —NH—S(═O)₂-haloC₁₋₄alkyl, C₁₋₄alkyl    substituted with —NH—S(═O)₂—NR¹⁴R¹⁵, R¹³, —C(═O)—R¹³, C₁₋₄alkyl    substituted with R¹³, phenyl optionally substituted with R¹⁶,    phenylC₁₋₆alkyl wherein the phenyl is optionally substituted with    R¹⁶, a 5 or 6-membered aromatic monocyclic heterocyclyl containing    at least one heteroatom selected from N, O or S wherein said    heterocyclyl is optionally substituted with R¹⁶; or when two of the    substituents of R⁹ are attached to the same atom, they may be taken    together to form a 4 to 7-membered saturated monocyclic heterocyclyl    containing at least one heteroatom selected from N, O or S;-   R¹⁰ and R¹¹ each independently represent hydrogen, carboxyl,    C₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵,    C₁₋₆alkyl substituted with —C(═O)—NR¹⁴R¹⁵, haloC₁₋₆alkyl,    hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy,    C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be    substituted with one or two hydroxyl groups, R⁶, C₁₋₆alkyl    substituted with R⁶, —C(═O)—R⁶, —C(═O)—C₁₋₆alkyl,    —C(═O)-hydroxyC₁₋₆alkyl, —C(═O)-haloC₁₋₆alkyl,    —C(═O)-hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with —Si(CH₃)₃,    —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl    substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,    C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl    substituted with —NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted    with —NH—S(═O)₂—NR¹⁴R¹⁵;-   R¹² represents hydrogen or C₁₋₄alkyl optionally substituted with    C₁₋₄alkoxy;-   R¹³ represents C₃₋₈cycloalkyl or a saturated 4 to 6-membered    monocyclic heterocyclyl containing at least one heteroatom selected    from N, O or S, wherein said C₃₋₈cycloalkyl or monocyclic    heterocyclyl is optionally substituted with 1, 2 or 3 substituents    each independently selected from halogen, hydroxyl, C₁₋₆alkyl,    —C(═O)—C₁₋₆alkyl, C₁₋₆alkoxy, or —NR¹⁴R¹⁵;-   R¹⁴ and R¹⁵ each independently represent hydrogen, or haloC₁₋₄alkyl,    or C₁₋₄alkyl optionally substituted with a substituent selected from    hydroxyl, C₁₋₄alkoxy, amino or mono- or di(C₁₋₄alkyl)amino;-   R¹⁶ represents hydroxyl, halogen, cyano, C₁₋₄alkyl, C₁₋₄alkoxy,    —NR¹⁴R¹⁵ or —C(═O)NR¹⁴R¹⁵;-   the N-oxides thereof, the pharmaceutically acceptable salts thereof    or the solvates thereof.

In one embodiment there is provided compounds of formula (I⁰):

including any stereochemically isomeric form thereof, wherein

-   n represents an integer equal to 0, 1, 2, 3 or 4;-   R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl, hydroxyC₁₋₆alkyl,    haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein    each C₁₋₆alkyl may optionally be substituted with one or two    hydroxyl groups, C₁₋₆alkyl substituted with —NR⁴R⁵, C₁₋₆alkyl    substituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl,    —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with    —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,    C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted    with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with    —NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkyl    substituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶,    C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkyl substituted with    —P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂;-   each R² is independently selected from halogen, cyano, C₁₋₁₄alkyl,    C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,    hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy,    hydroxyhaloC₁₋₄alkyl, hydroxyhaloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,    haloC₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl    may optionally be substituted with one or two hydroxyl groups,    hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl, R¹³, C₁₋₄alkyl substituted with R¹³,    C₁₋₄alkyl substituted with —C(═O)—R¹³, C₁₋₄alkoxy substituted with    R¹³, C₁₋₄alkoxy substituted with —C(═O)—R¹³, —C(═O)—R¹³, C₁₋₄alkyl    substituted with —NR⁷R⁸, C₁₋₄alkyl substituted with —C(═O)—NR⁷R⁸,    C₁₋₄alkoxy substituted with —NR⁷R⁸, C₁₋₄alkoxy substituted with    —C(═O)—NR⁷R⁸, —NR⁷R⁸ or —C(═O)—NR⁷R⁸;-   R³ represents hydroxyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxy    substituted with —NR¹⁰R¹¹, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,    haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, hydroxyC₂₋₆alkenyl,    hydroxyC₂₋₆alkynyl, hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkyl    substituted with carboxyl, C₁₋₆alkyl substituted with    —C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl,    C₁₋₆alkyl substituted with C₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl    substituted with C₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted    with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl    may optionally be substituted with one or two hydroxyl groups,    C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynyl substituted    with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹, C₁₋₆alkyl    substituted with —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and    R⁹, C₂₋₆alkenyl substituted with R⁹, C₂₋₆alkynyl substituted with    R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted    with —NR¹⁰R¹¹, C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl    substituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with    one or two halogens and —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹²,    C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted    with —O—C(═O)—NR¹⁰R¹¹, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl,    —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl,    C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl    substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with    —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with    —NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ or    C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂;-   R⁴ and R⁵ independently represent hydrogen, C₁₋₆alkyl,    hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,    C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be    substituted with one or two hydroxyl groups, —S(═O)₂—C₁₋₆alkyl,    —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with    —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,    C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted    with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with    —NH—S(═O)₂—NR¹⁴R¹⁵, R¹³ or C₁₋₆alkyl substituted with R¹³;-   R⁶ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to    7-membered monocyclic heterocyclyl containing at least one    heteroatom selected from N, O or S; said C₃₋₈cycloalkyl,    C₃₋₈cycloalkenyl, phenyl, 4 to 7-membered monocyclic heterocyclyl,    optionally and each independently being substituted by 1, 2, 3, 4 or    5 substituents, each substituent independently being selected from    cyano, C₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyl, carboxyl,    hydroxyC₁₋₆alkyl, halogen, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkyl-O—C(═O)—, —NR¹⁴R¹⁵,    —C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkyl    substituted with —C(═O)—NR¹⁴R¹⁵, —S(═O)₂—C₁₋₆alkyl,    —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with    —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,    C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted    with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted with    —NH—S(═O)₂—NR¹⁴R¹⁵;-   R⁷ and R⁸ independently represent hydrogen, C₁₋₆alkyl,    hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl or    C₁₋₆alkoxyC₁₋₆alkyl;-   R⁹ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, naphthyl, or    3 to 12 membered monocyclic or bicyclic heterocyclyl containing at    least one heteroatom selected from N, O or S, said C₃₋₈cycloalkyl,    C₃₋₈cycloalkenyl, phenyl, naphthyl, or 3 to 12 membered monocyclic    or bicyclic heterocyclyl each optionally and each independently    being substituted with 1, 2, 3, 4 or 5 substituents, each    substituent independently being selected from ═O, C₁₋₄alkyl,    hydroxyl, carboxyl, hydroxyC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl,    C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkyl substituted with C₁₋₄alkyl-O—C(═O)—,    C₁₋₄alkyl-C(═O)—, C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl may    optionally be substituted with one or two hydroxyl groups, halogen,    haloC₁₋₄alkyl, hydroxyhaloC₁₋₄alkyl, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵,    C₁₋₄alkyl substituted with —NR¹⁴R¹⁵, C₁₋₄alkyl substituted with    —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkoxy, —S(═O)₂—C₁₋₄alkyl,    —S(═O)₂-haloC₁₋₄alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with    —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with —NH—S(═O)₂—C₁₋₄alkyl,    C₁₋₄alkyl substituted with —NH—S(═O)₂-haloC₁₋₄alkyl, C₁₋₄alkyl    substituted with —NH—S(═O)₂—NR¹⁴R¹⁵, R¹³, —C(═O)—R¹³, C₁₋₄alkyl    substituted with R¹³, phenyl optionally substituted with R¹⁶,    phenylC₁₋₆alkyl wherein the phenyl is optionally substituted with    R¹⁶, a 5 or 6-membered aromatic monocyclic heterocyclyl containing    at least one heteroatom selected from N, O or S wherein said    heterocyclyl is optionally substituted with R¹⁶; or when two of the    substituents of R⁹ are attached to the same atom, they may be taken    together to form a 4 to 7-membered saturated monocyclic heterocyclyl    containing at least one heteroatom selected from N, O or S;-   R¹⁰ and R¹¹ each independently represent hydrogen, C₁₋₆alkyl,    cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, haloC₁₋₆alkyl,    hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein    each C₁₋₆alkyl may optionally be substituted with one or two    hydroxyl groups, R⁶, C₁₋₆alkyl substituted with R⁶, —C(═O)—R⁶,    —C(═O)—C₁₋₆alkyl, —C(═O)-hydroxyC₁₋₆alkyl, —C(═O)-haloC₁₋₆alkyl,    —C(═O)-hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with —Si(CH₃)₃,    —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl    substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,    C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl    substituted with —NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted    with —NH—S(═O)₂—NR¹⁴R¹⁴R¹⁵;-   R¹² represents hydrogen or C₁₋₄alkyl optionally substituted with    C₁₋₄alkoxy;-   R¹³ represents C₃₋₈cycloalkyl or a saturated 4 to 6-membered    monocyclic heterocyclyl containing at least one heteroatom selected    from N, O or S, wherein said C₃₋₈cycloalkyl or monocyclic    heterocyclyl is optionally substituted with 1, 2 or 3 substituents    each independently selected from halogen, hydroxyl, C₁₋₆alkyl,    —C(═O)—C₁₋₆alkyl, C₁₋₆alkoxy, or —NR¹⁴R¹⁵;-   R¹⁴ and R¹⁵ each independently represent hydrogen, or haloC₁₋₄alkyl,    or C₁₋₄alkyl optionally substituted with a substituent selected from    hydroxyl, C₁₋₄alkoxy, amino or mono- or di(C₁₋₄alkyl)amino;-   R¹⁶ represents hydroxyl, halogen, cyano, C₁₋₄alkyl, C₁₋₄alkoxy,    —NR¹⁴R¹⁵ or —C(═O)NR¹⁴R¹⁵;    the N-oxides thereof, the pharmaceutically acceptable salts thereof    or the solvates thereof.

WO2006/092430, WO2008/003702, WO01/68047, WO2005/007099, WO2004/098494,WO2009/141386, WO 2004/030635, WO 2008/141065, WO 2011/026579, WO2011/028947 and WO 00/42026 which each disclose a series of heterocyclylderivatives.

DETAILED DESCRIPTION OF THE INVENTION

Unless the context indicates otherwise, references to formula (I) in allsections of this document (including the uses, methods and other aspectsof the invention) include references to all other sub-formula (e.g. I′,I″, I′″, I⁰, I⁰′, I⁰″, I⁰′″), sub-groups, preferences, embodiments andexamples as defined herein.

The prefix “C_(x-y)” (where x and y are integers) as used herein refersto the number of carbon atoms in a given group. Thus, a C₁₋₆alkyl groupcontains from 1 to 6 carbon atoms, a C₃₋₆cycloalkyl group contains from3 to 6 carbon atoms, a C₁₋₄alkoxy group contains from 1 to 4 carbonatoms, and so on.

The term ‘halo’ or ‘halogen’ as used herein refers to a fluorine,chlorine, bromine or iodine atom.

The term ‘C₁₋₄alkyl’, or ‘C₁₋₆alkyl’ as used herein as a group or partof a group refers to a linear or branched saturated hydrocarbon groupcontaining from 1 to 4 or 1 to 6 carbon atoms. Examples of such groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl and thelike.

The term ‘C₂₋₄alkenyl’ or ‘C₂₋₆alkenyl’ as used herein as a group orpart of a group refers to a linear or branched hydrocarbon groupcontaining from 2 to 4 or 2 to 6 carbon atoms and containing a carboncarbon double bond.

The term ‘C₂₋₄alkynyl’ or ‘C₂₋₆alkynyl’ as used herein as a group orpart of a group refers to a linear or branched hydrocarbon group havingfrom 2 to 4 or 2 to 6 carbon atoms and containing a carbon carbon triplebond.

The term ‘C₁₋₄alkoxy’ or ‘C₁₋₆alkoxy’ as used herein as a group or partof a group refers to an —O—C₁₋₄alkyl group or an —O—C₁₋₆alkyl groupwherein C₁₋₄alkyl and C₁₋₆alkyl are as defined herein. Examples of suchgroups include methoxy, ethoxy, propoxy, butoxy, and the like.

The term ‘C₁₋₄alkoxyC₁₋₄alkyl’ or ‘C₁₋₆alkoxyC₁₋₆alkyl’ as used hereinas a group or part of a group refers to a C₁₋₄alkyl-O—C₁₋₄alkyl group ora C₁₋₆alkyl-O—C₁₋₆alkyl group wherein C₁₋₄alkyland C₁₋₆alkyl are asdefined herein. Examples of such groups include methoxyethyl,ethoxyethyl, propoxymethyl, butoxypropyl, and the like.

The term ‘C₃₋₈cycloalkyl’ as used herein refers to a saturatedmonocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of suchgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl and the like.

The term ‘C₃₋₈cycloalkenyl’ as used herein refers to a monocyclichydrocarbon ring of 3 to 8 carbon atoms having a carbon carbon doublebond.

The term ‘hydroxyC₁₋₄alkyl’ or ‘hydroxyC₁₋₆alkyl’ as used herein as agroup or part of a group refers to a C₁₋₄alkyl or C₁₋₆alkyl group asdefined herein wherein one or more than one hydrogen atom is replacedwith a hydroxyl group. The terms ‘hydroxyC₁₋₄alkyl’ or‘hydroxyC₁₋₆alkyl’ therefore include monohydroxyC₁₋₄alkyl,monohydroxyC₁₋₆alkyl and also polyhydroxyC₁₋₄alkyl andpolyhydroxyC₁₋₆alkyl. There may be one, two, three or more hydrogenatoms replaced with a hydroxyl group, so the hydroxyC₁₋₄alkyl orhydroxyC₁₋₆alkyl may have one, two, three or more hydroxyl groups.Examples of such groups include hydroxymethyl, hydroxyethyl,hydroxypropyl and the like.

The term ‘haloC₁₋₄alkyl’ or ‘haloC₁₋₆alkyl’ as used herein as a group orpart of a group refers to a C₁₋₄alkyl or C₁₋₆alkyl group as definedherein wherein one or more than one hydrogen atom is replaced with ahalogen. The term ‘haloC₁₋₄alkyl’ or ‘haloC₁₋₆alkyl’ therefore includemonohaloC₁₋₄alkyl, monohaloC₁₋₆alkyl and also polyhaloC₁₋₄alkyl andpolyhaloC₁₋₆alkyl. There may be one, two, three or more hydrogen atomsreplaced with a halogen, so the haloC₁₋₄alkyl or haloC₁₋₆alkyl may haveone, two, three or more halogens. Examples of such groups includefluoroethyl, fluoromethyl, trifluoromethyl or trifluoroethyl and thelike.

The term ‘hydroxyhaloC₁₋₄alkyl’ or ‘hydroxyhaloC₁₋₆alkyl’ as used hereinas a group or part of a group refers to a C₁₋₄alkyl or C₁₋₆alkyl groupas defined herein wherein one or more than one hydrogen atom is replacedwith a hydroxyl group and one or more than one hydrogen atom is replacedwith a halogen. The term ‘hydroxyhaloC₁₋₄alkyl’ or‘hydroxyhaloC₁₋₆alkyl’ therefore refers to a C₁₋₄alkyl or C₁₋₆alkylgroup wherein one, two, three or more hydrogen atoms are replaced with ahydroxyl group and one, two, three or more hydrogen atoms are replacedwith a halogen.

The term ‘hydroxyC₁₋₄alkoxy’ or ‘hydroxyC₁₋₆alkoxy’ as used herein as agroup or part of a group refers to an —O—C₁₋₄alkyl group or an—O—C₁₋₆alkyl group wherein the C₁₋₄alkyl and C₁₋₆alkyl group is asdefined above and one or more than one hydrogen atom of the C₁₋₄alkyl orC₁₋₆alkyl group is replaced with a hydroxyl group. The term‘hydroxyC₁₋₄alkoxy’ or ‘hydroxyC₁₋₆alkoxy’ therefore includemonohydroxyC₁₋₄alkoxy, monohydroxyC₁₋₆alkoxy and alsopolyhydroxyC₁₋₄alkoxy and polyhydroxyC₁₋₆alkoxy.

There may be one, two, three or more hydrogen atoms replaced with ahydroxyl group so the hydroxyC₁₋₄alkoxy or hydroxyC₁₋₆alkoxy may haveone, two, three or more hydroxyl groups. Examples of such groups includehydroxymethoxy, hydroxyethoxy, hydroxypropoxy and the like.

The term ‘haloC₁₋₄alkoxy’ or ‘haloC₁₋₆alkoxy’ as used herein as a groupor part of a group refers to a —O—C₁₋₄alkyl group or a —O—C₁₋₆ alkylgroup as defined herein wherein one or more than one hydrogen atom isreplaced with a halogen. The terms ‘haloC₁₋₄alkoxy’ or ‘haloC₁₋₆alkoxy’therefore include monohaloC₁₋₄alkoxy, monohaloC₁₋₆alkoxy and alsopolyhaloC₁₋₄alkoxy and polyhaloC₁₋₆alkoxy. There may be one, two, threeor more hydrogen atoms replaced with a halogen, so the haloC₁₋₄alkoxy orhaloC₁₋₆alkoxy may have one, two, three or more halogens. Examples ofsuch groups include fluoroethyloxy, difluoromethoxy or trifluoromethoxyand the like.

The term ‘hydroxyhaloC₁₋₄alkoxy’ as used herein as a group or part of agroup refers to an —O—C₁₋₄alkyl group wherein the C₁₋₄alkyl group is asdefined herein and wherein one or more than one hydrogen atom isreplaced with a hydroxyl group and one or more than one hydrogen atom isreplaced with a halogen. The term ‘hydroxyhaloC₁₋₄alkoxy’ thereforerefers to a —O—C₁₋₄alkyl group wherein one, two, three or more hydrogenatoms are replaced with a hydroxyl group and one, two, three or morehydrogen atoms are replaced with a halogen.

The term ‘haloC₁₋₄alkoxyC₁₋₄alkyl’ as used herein as a group or part ofa group refers to a C₁₋₄alkyl-O—C₁₋₄alkyl group wherein C₁₋₄alkyl is asdefined herein and wherein in one or both of the C₁₋₄alkyl groups one ormore than one hydrogen atom is replaced with a halogen. The term‘haloC₁₋₄alkoxyC₁₋₄alkyl’ therefore refers to a C₁₋₄alkyl-O—C₁₋₄alkylgroup wherein in one or both of the C₁₋₄alkyl groups one, two, three ormore hydrogen atoms are replaced with a halogen and wherein C₁₋₄ alkylis as defined herein. Preferably, in one of the C₁₋₄alkyl groups one ormore than one hydrogen atom is replaced with a halogen. Preferably,haloC₁₋₄alkoxyC₁₋₄alkyl means C₁₋₄alkyl substituted with haloC₁₋₄alkoxy.

The term ‘hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl’ as used herein refers to aC₁₋₄alkyl-O—C₁₋₄alkyl group wherein C₁₋₄alkyl is as defined herein andwherein in one or both of the C₁₋₄alkyl groups one or more than onehydrogen atom is replaced with a hydroxyl group and one or more than onehydrogen atom is replaced with a halogen. The terms‘hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl’ therefore refers to aC₁₋₄alkyl-O—C₁₋₄alkyl group wherein in one or both of the C₁₋₄alkylgroups one, two, three or more hydrogen atoms are replaced with ahydroxyl group and one, two, three or more hydrogen atoms are replacedwith a halogen and wherein C₁₋₄alkyl is as defined herein.

The term ‘hydroxyC₂₋₆alkenyl’ as used herein refers to a C₂₋₆alkenylgroup wherein one or more than one hydrogen atom is replaced with ahydroxyl group and wherein C₂₋₆alkenyl is as defined herein.

The term ‘hydroxyC₂₋₆alkynyl’ as used herein refers to a C₂₋₆alkynylgroup wherein one or more than one hydrogen atom is replaced with ahydroxyl group and wherein C₂₋₆alkynyl is as defined herein.

The term phenylC₁₋₆alkyl as used herein refers to a C₁₋₆alkyl group asdefined herein which is substituted with one phenyl group.

The term cyanoC₁₋₄alkyl or cyanoC₁₋₆alkyl as used herein refers to aC₁₋₄alkyl or C₁₋₆alkyl group as defined herein which is substituted withone cyano group.

The term “heterocyclyl” as used herein shall, unless the contextindicates otherwise, include both aromatic and non-aromatic ringsystems. Thus, for example, the term “heterocyclyl group” includeswithin its scope aromatic, non-aromatic, unsaturated, partiallysaturated and fully saturated heterocyclyl ring systems. In general,unless the context indicates otherwise, such groups may be monocyclic orbicyclic and may contain, for example, 3 to 12 ring members, moreusually 5 to 10 ring members. Reference to 4 to 7 ring members include4, 5, 6 or 7 atoms in the ring and reference to 4 to 6 ring membersinclude 4, 5, or 6 atoms in the ring. Examples of monocyclic groups aregroups containing 3, 4, 5, 6, 7 and 8 ring members, more usually 3 to 7,and preferably 5, 6 or 7 ring members, more preferably 5 or 6 ringmembers. Examples of bicyclic groups are those containing 8, 9, 10, 11and 12 ring members, and more usually 9 or 10 ring members. Wherereference is made herein to heterocyclyl groups, the heterocyclyl ringcan, unless the context indicates otherwise, be optionally substituted(i.e. unsubstituted or substituted) by one or more substituents asdiscussed herein.

The heterocyclyl groups can be heteroaryl groups having from 5 to 12ring members, more usually from 5 to 10 ring members. The term“heteroaryl” is used herein to denote a heterocyclyl group havingaromatic character. The term “heteroaryl” embraces polycyclic (e.g.bicyclic) ring systems wherein one or more rings are non-aromatic,provided that at least one ring is aromatic. In such polycyclic systems,the group may be attached by the aromatic ring, or by a non-aromaticring.

Examples of heteroaryl groups are monocyclic and bicyclic groupscontaining from five to twelve ring members, and more usually from fiveto ten ring members. The heteroaryl group can be, for example, a fivemembered or six membered monocyclic ring or a bicyclic structure formedfrom fused five and six membered rings or two fused six membered rings,or two fused five membered rings. Each ring may contain up to about fiveheteroatoms typically selected from nitrogen, sulphur and oxygen.Typically the heteroaryl ring will contain up to 4 heteroatoms, moretypically up to 3 heteroatoms, more usually up to 2, for example asingle heteroatom. In one embodiment, the heteroaryl ring contains atleast one ring nitrogen atom. The nitrogen atoms in the heteroaryl ringscan be basic, as in the case of an imidazole or pyridine, or essentiallynon-basic as in the case of an indole or pyrrole nitrogen. In generalthe number of basic nitrogen atoms present in the heteroaryl group,including any amino group substituents of the ring, will be less thanfive.

Examples of five membered heteroaryl groups include but are not limitedto pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole,oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole,triazole and tetrazole groups.

Examples of six membered heteroaryl groups include but are not limitedto pyridine, pyrazine, pyridazine, pyrimidine and triazine.

A bicyclic heteroaryl group may be, for example, a group selected from:

-   -   a) a benzene ring fused to a 5- or 6-membered ring containing 1,        2 or 3 ring heteroatoms;    -   b) a pyridine ring fused to a 5- or 6-membered ring containing        0, 1, 2 or 3 ring heteroatoms;    -   c) a pyrimidine ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   d) a pyrrole ring fused to a 5- or 6-membered ring containing 0,        1, 2 or 3 ring heteroatoms;    -   e) a pyrazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   f) an imidazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   g) an oxazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   h) an isoxazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   i) a thiazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   j) an isothiazole ring fused to a 5- or 6-membered ring        containing 0, 1 or 2 ring heteroatoms;    -   k) a thiophene ring fused to a 5- or 6-membered ring containing        0, 1, 2 or 3 ring heteroatoms;    -   l) a furan ring fused to a 5- or 6-membered ring containing 0,        1, 2 or 3 ring heteroatoms;    -   m) a cyclohexyl ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms; and    -   n) a cyclopentyl ring fused to a 5- or 6-membered ring        containing 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a fivemembered ring fused to another five membered ring include but are notlimited to imidazothiazole (e.g. imidazo[2,1-b]thiazole) andimidazoimidazole (e.g. imidazo[1,2-a]imidazole).

Particular examples of bicyclic heteroaryl groups containing a sixmembered ring fused to a five membered ring include but are not limitedto benzofuran, benzothiophene, benzimidazole, benzoxazole,isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole,isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline,purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g.pyrazolo[1,5-a]pyrimidine), triazolopyrimidine (e.g.[1,2,4]triazolo[1,5-a]pyrimidine), benzodioxole, imidazopyridine andpyrazolopyridine (e.g. pyrazolo[1,5-a]pyridine) groups.

Particular examples of bicyclic heteroaryl groups containing two fusedsix membered rings include but are not limited to quinoline,isoquinoline, chroman, thiochroman, chromene, isochromene, chroman,isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine,pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine,naphthyridine and pteridine groups.

Examples of polycyclic heteroaryl groups containing an aromatic ring anda non-aromatic ring include, tetrahydroisoquinoline,tetrahydroquinoline, dihydrobenzthiene, dihydrobenzfuran,2,3-dihydro-benzo[1,4]dioxine, benzo[1,3]dioxole,4,5,6,7-tetrahydrobenzofuran, tetrahydrotriazolopyrazine (e.g.5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine), indoline and indanegroups.

A nitrogen-containing heteroaryl ring must contain at least one ringnitrogen atom. Each ring may, in addition, contain up to about fourother heteroatoms typically selected from nitrogen, sulphur and oxygen.Typically the heteroaryl ring will contain up to 3 heteroatoms, forexample 1, 2 or 3, more usually up to 2 nitrogens, for example a singlenitrogen. The nitrogen atoms in the heteroaryl rings can be basic, as inthe case of an imidazole or pyridine, or essentially non-basic as in thecase of an indole or pyrrole nitrogen. In general the number of basicnitrogen atoms present in the heteroaryl group, including any aminogroup substituents of the ring, will be less than five.

Examples of nitrogen-containing heteroaryl groups include, but are notlimited to, pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl,thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl,furazanyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazole,benzthiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl,indolizinyl, isoindolinyl, purinyl (e.g., adenine [6-aminopurine],guanine [2-amino-6-hydroxypurine]), indazolyl, quinolizinyl,benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl.

Examples of nitrogen-containing polycyclic heteroaryl groups containingan aromatic ring and a non-aromatic ring includetetrahydroisoquinolinyl, tetrahydroquinolinyl, and indolinyl.

The term “non-aromatic group” embraces, unless the context indicatesotherwise, unsaturated ring systems without aromatic character,partially saturated and fully saturated heterocyclyl ring systems. Theterms “unsaturated” and “partially saturated” refer to rings wherein thering structure(s) contains atoms sharing more than one valence bond i.e.the ring contains at least one multiple bond e.g. a C═C, C≡C or N═Cbond. The term “fully saturated” refers to rings where there are nomultiple bonds between ring atoms. Saturated heterocyclyl groups includepiperidine, morpholine, thiomorpholine, piperazine. Partially saturatedheterocyclyl groups include pyrazolines, for example 2-pyrazoline and3-pyrazoline.

Examples of non-aromatic heterocyclyl groups are groups having from 3 to12 ring members, more usually 5 to 10 ring members. Such groups can bemonocyclic or bicyclic, for example, and typically have from 1 to 5heteroatom ring members (more usually 1, 2, 3 or 4 heteroatom ringmembers), usually selected from nitrogen, oxygen and sulphur. Theheterocyclyl groups can contain, for example, cyclic ether moieties(e.g. as in tetrahydrofuran and dioxane), cyclic thioether moieties(e.g. as in tetrahydrothiophene and dithiane), cyclic amine moieties(e.g. as in pyrrolidine), cyclic amide moieties (e.g. as inpyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ureas (e.g.as in imidazolidin-2-one) cyclic ester moieties (e.g. as inbutyrolactone), cyclic sulphones (e.g. as in sulpholane and sulpholene),cyclic sulphoxides, cyclic sulphonamides and combinations thereof (e.g.thiomorpholine).

Particular examples include morpholine, piperidine (e.g. 1-piperidinyl,2-piperidinyl, 3-piperidinyl and 4-piperidinyl), piperidone, pyrrolidine(e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone,azetidine, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran,dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene,dioxane, tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline,imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine,piperazone, piperazine, and N-alkyl piperazines such as N-methylpiperazine. In general, preferred non-aromatic heterocyclyl groupsinclude saturated groups such as piperidine, pyrrolidine, azetidine,morpholine, piperazine and N-alkyl piperazines.

In a nitrogen-containing non-aromatic heterocyclyl ring the ring mustcontain at least one ring nitrogen atom. The heterocylic groups cancontain, for example cyclic amine moieties (e.g. as in pyrrolidine),cyclic amides (such as a pyrrolidinone, piperidone or caprolactam),cyclic sulphonamides (such as an isothiazolidine 1,1-dioxide,[1,2]thiazinane 1,1-dioxide or [1,2]thiazepane 1,1-dioxide) andcombinations thereof. Particular examples of nitrogen-containingnon-aromatic heterocyclyl groups include aziridine, morpholine,thiomorpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl,3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 1-pyrrolidinyl,2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, dihydrothiazole,imidazoline, imidazolidinone, oxazoline, thiazoline,6H-1,2,5-thiadiazine, 2-pyrazoline, 3-pyrazoline, pyrazolidine,piperazine, and N-alkyl piperazines such as N-methyl piperazine.

The heterocyclyl groups can be polycyclic fused ring systems or bridgedring systems such as the oxa- and aza analogues of bicycloalkanes,tricycloalkanes (e.g. adamantane and oxa-adamantane). For an explanationof the distinction between fused and bridged ring systems, see AdvancedOrganic Chemistry, by Jerry March, 4^(th) Edition, Wiley Interscience,pages 131-133, 1992.

The heterocyclyl groups can each be unsubstituted or substituted by oneor more substituent groups. For example, heterocyclyl groups can beunsubstituted or substituted by 1, 2, 3 or 4 substituents. Where theheterocyclyl group is monocyclic or bicyclic, typically it isunsubstituted or has 1, 2 or 3 substituents.

The term ‘aryl’ as used herein refers to carbocyclyl aromatic groupsincluding phenyl, naphthyl, indenyl, and tetrahydronaphthyl groups.

In one embodiment R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl,hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, C₁₋₆alkyl substituted with —NR⁴R⁵,C₁₋₆alkyl substituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkylsubstituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶,C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkyl substituted with—P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂.

In one embodiment R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl,hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groups,C₁₋₆alkyl substituted with —NR⁴R⁵, C₁₋₆alkyl substituted with—C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substitutedwith —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl,R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkyl substituted with —C(═O)—R⁶,hydroxyC₁₋₆alkyl substituted with R⁶, or C₁₋₆alkyl substituted with—Si(CH₃)₃.

In one embodiment R¹ represents hydrogen.

In one embodiment R¹ represents C₁₋₆alkyl. R¹ may represent —CH₃, —CD₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)₂, —CH₂CH(CH₃)₂. In oneembodiment R¹ represents —CH₃. In another embodiment R¹ represents —CD₃.

In one embodiment R¹ represents C₂₋₄alkenyl. R¹ may represent—CH₂—CH═CH₂.

In one embodiment R¹ represents hydroxyC₁₋₆alkyl. R¹ may represent—CH₂CH₂OH, —CH₂C(CH₃)₂OH or CH₂CHOHCH₂OH.

In one embodiment R¹ represents haloC₁₋₆alkyl. R¹ may represent—CH₂CH₂F, CH₂CH₂CH₂C₁ or CH₂CH₂Br.

In one embodiment R¹ represents C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groups.R¹ may represent —CH₂CH₂OCH₃.

In one embodiment R¹ represents C₁₋₆alkyl substituted with —NR⁴R⁵.

In one embodiment when R¹ represents C₁₋₆alkyl substituted with —NR⁴R⁵,R⁴ and R⁵ each represent hydrogen. R¹ may represent —CH₂CH₂NH₂ or—CH₂CH₂CH₂NH₂.

In another embodiment when R¹ represents C₁₋₆alkyl substituted with—NR⁴R⁵, one of R⁴ and R⁵ represents hydrogen and the other representsC₁₋₆alkyl, for example —CH₃. R¹ may represent —CH₂CH₂NHCH₃.

In another embodiment when R¹ represents C₁₋₆alkyl substituted with—NR⁴R⁵, one of R⁴ and R⁵ represents hydrogen and the other represents—S(═O)₂—NR¹⁴R¹⁵ where R¹⁴ and R¹⁵ each represent C₁₋₄alkyl optionallysubstituted with hydroxyl, for example —CH₃. R¹ may represent—CH₂CH₂NHS(═O)₂N(CH₃)₂.

In another embodiment when R¹ represents C₁₋₆alkyl substituted with—NR⁴R⁵, one of R⁴ and R⁵ represents hydrogen and the other represents—S(═O)₂—C₁₋₆alkyl. R¹ may represent —CH₂CH₂NHS(═O)₂CH₃.

In one embodiment R¹ represents C₁₋₆alkyl substituted with —C(═O)—NR⁴R⁵.

In one embodiment when R¹ represents C₁₋₆alkyl substituted with—C(═O)—NR⁴R⁵, R⁴ and R⁵ each represent C₁₋₆alkyl, for example —CH₃. R¹may represent —CH₂C(═O)N(CH₃)₂.

In another embodiment when R¹ represents C₁₋₆alkyl substituted with—C(═O)—NR⁴R⁵, one of R⁴ and R⁵ represents hydrogen and the otherrepresents C₁₋₆alkyl, for example —CH₃. R¹ may represent —CH₂C(═O)NHCH₃or —C(CH₃)₂C(═O)NHCH₃.

In another embodiment when R¹ represents C₁₋₆alkyl substituted with—C(═O)—NR⁴R⁵, one of R⁴ and R⁵ represents hydrogen and the otherrepresents hydroxyC₁₋₆alkyl, for example —CH₂CH₂OH. R¹ may represent—C(CH₃)₂C(═O)NHCH₂CH₂OH or —CH₂C(═O)NHCH₂CH₂OH.

In another embodiment when R¹ represents C₁₋₆alkyl substituted with—C(═O)—NR⁴R⁵, one of R⁴ and R⁵ represents hydrogen and the otherrepresents C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally besubstituted with one or two hydroxyl groups, for example —CH₂CH₂OCH₃. R¹may represent —CH₂C(═O)NHCH₂CH₂OCH₃ or —C(CH₃)₂C(═O)NHCH₂CH₂OCH₃.

In another embodiment when R¹ represents C₁₋₆alkyl substituted with—C(═O)—NR⁴R⁵, one of R⁴ and R⁵ represents hydrogen and the otherrepresents C₁₋₆alkyl substituted with R¹³. R¹³ may represent a saturated5 membered monocyclic heterocyclyl containing at least one nitrogenheteroatom, for example pyrrolidine. R¹ may represent—CH₂—C(═O)—NH—CH₂—CH₂— (pyrrolidin-1-yl).

In another embodiment when R¹ represents C₁₋₆alkyl substituted with—C(═O)—NR⁴R⁵, one of R⁴ and R⁵ represents hydrogen and the otherrepresents C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl. R¹ mayrepresent —CH₂CH₂CH₂NHCH₂CH₂—S(═O)₂—CH₃.

In one embodiment R¹ represents —S(═O)₂—C₁₋₆alkyl. R¹ may represent—S(═O)₂—CH₃.

In one embodiment R¹ represents —S(═O)₂—NR¹⁴R¹⁵. R¹⁴ and R¹⁵ may eachrepresent C₁₋₄alkyl optionally substituted with hydroxyl, for exampleR¹⁴ and R¹⁵ may both represent —CH₃. R¹ may represent —S(═O)₂—N(CH₃)₂.

In one embodiment R¹ represents C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl. R¹ may represent —CH₂CH₂S(═O)₂—CH₃.

In one embodiment R¹ represents C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl. R¹ may represent —CH₂CH₂NHS(═O)₂—CH₃.

In one embodiment R¹ represents R⁶. R⁶ may represent a saturated 4, 5 or6 membered monocyclic heterocyclyl containing at least one heteroatomselected from N, O or S, which may optionally be substituted.

In one embodiment when R¹ represents R⁶, R⁶ represents piperidinyl, forexample 4-piperidinyl.

In one embodiment when R¹ represents R⁶, R⁶ representstetrahydropyranyl, for example 2-tetrahydropyranyl or4-tetrahydropyranyl.

In one embodiment when R¹ represents R⁶, R⁶ representstetrahydrofuranyl, for example 3-tetrahydrofuranyl.

In another embodiment when R¹ represents R⁶, R⁶ represents azetidinylsubstituted by one hydroxyC₁₋₆alkyl group. The hydroxyC₁₋₆alkyl groupmay be —CH₂CH₂OH. R⁶ may represent

In another embodiment when R¹ represents R⁶, R⁶ represents piperidinylsubstituted by one C₁₋₆alkyl-O—C(═O)— group. The C₁₋₆alkyl-O—C(═O)—group may be (CH₃)₃C—O—C(═O)—. R⁶ may represent 4-piperidinylsubstituted on the nitrogen atom with (CH₃)₃C—O—C(═O)—. In anotherembodiment when R¹ represents R⁶, R⁶ represents piperidinyl substitutedby one —S(═O)₂—C₁₋₆alkyl group. The —S(═O)₂—C₁₋₆alkyl group may be—S(═O)₂CH₃. R⁶ may represent 4-piperidinyl substituted on the nitrogenatom with —S(═O)₂CH₃. In another embodiment when R¹ represents R⁶, R⁶represents piperidinyl substituted by one C₁₋₆alkyl group. The C₁₋₆alkylgroup may be —CH₃. R⁶ may represent 4-piperidinyl substituted on thenitrogen atom with —CH₃.

In one embodiment R¹ represents C₁₋₆alkyl substituted with R⁶. R⁶ mayrepresent a saturated 4, 5 or 6 membered monocyclic heterocyclylcontaining at least one heteroatom selected from N, O or S, which mayoptionally be substituted. R⁶ may represent pyrrolidinyl, thiophenyl,piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl. R¹ mayrepresent methyl or ethyl each substituted with 4-piperidinyl,4-piperazinyl, 1-pyrrolidinyl or 4-tetrahydropyranyl. R¹ may representpropyl substituted with morpholinyl where the morpholinyl is linked tothe propyl through the N heteroatom. In another embodiment theheterocyclyl may be substituted by one substituent selected fromhalogen, C₁₋₆alkyl, hydroxyl, hydroxyC₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkyl-O—C(═O)—. The substituent may be —Cl, —CH₃, —OH, —CH₂CH₂OH,—CH₂CH₂CH₂OH, —OCH₃, (CH₃)₃C—O—C(═O)—.

R¹ may represent methyl, ethyl or propyl each substituted with4-piperidinyl substituted on the nitrogen atom with (CH₃)₃C—O—C(═O)—,4-piperidinyl substituted on the nitrogen atom with —CH₃, 4-piperazinylsubstituted on the nitrogen atom (N1) with (CH₃)₃C—O—C(═O)—,4-piperazinyl substituted on the nitrogen atom (N1) with —CH₂CH₂OH,4-piperazinyl substituted on the nitrogen atom (N1) with —CH₂CH₂CH₂OH,4-piperidinyl substituted in the 4 position by —OH, or 4-piperidinylsubstituted in the 4 position by —O—CH₃. R¹ may represent methylsubstituted with 2-thiophenyl substituted in the 5 position withchlorine. In another embodiment the heterocyclyl may be substituted bytwo substituents selected from hydroxyl, C₁₋₆alkoxy, C₁₋₆alkyl-O—C(═O)—.The substituent may be —OH, —OCH₃, (CH₃)₃C—O—C(═O)—. R¹ may representmethyl substituted with 4-piperidinyl substituted on the nitrogen atomwith (CH₃)₃C—O—C(═O)— and in the 4 position by —OH.

In one embodiment R¹ represents C₁₋₆alkyl substituted with —C(═O)—R⁶. R⁶may represent a saturated 4, 5 or 6 membered monocyclic heterocyclylcontaining at least one heteroatom selected from N, O or S, which mayoptionally be substituted. R⁶ may represent piperazinyl or pyrrolidinyl.

In one embodiment when R¹ represents C₁₋₆alkyl substituted with—C(═O)—R⁶, R⁶ represents piperazinyl. R¹ may represent—C(CH₃)₂—C(═O)-(piperazin-4-yl). In another embodiment when R¹represents C₁₋₆alkyl substituted with —C(═O)—R⁶, R⁶ representspiperazinyl substituted by one C₁₋₆alkyl-O—C(═O)— group, for exampleC(CH₃)₃—O—C(═O)—. R¹ may represent —C(CH₃)₂—C(═O)-(piperazin-4-yl)substituted on the nitrogen atom in the 1 position by C(CH₃)₃—O—C(═O)—.

In another embodiment when R¹ represents C₁₋₆alkyl substituted with—C(═O)—R⁶, R⁶ represents pyrrolidinyl substituted by one hydroxyl group.R¹ may represent —CH₂—C(═O)-(pyrrolidin-1-yl) substituted in the 3position by —OH.

In one embodiment R¹ represents hydroxyC₁₋₆alkyl substituted with R⁶, R⁶may represent a saturated 4, 5 or 6 membered monocyclic heterocyclylcontaining at least one heteroatom selected from N, O or S, which mayoptionally be substituted. R⁶ may represent piperidinyl, for example1-piperidinyl. R¹ may represent —CH₂CHOHCH₂-piperidin-1-yl.

In one embodiment R¹ represents C₁₋₆alkyl substituted with —Si(CH₃)₃. R¹may represent —CH₂Si(CH₃)₃.

In one embodiment R¹ represents cyanoC₁₋₄alkyl. R¹ may represent—CH₂CH₂CN.

In one embodiment each R^(1a) is independently selected from hydrogen,C₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₁₋₄alkyl substituted with amino or mono-or di(C₁₋₄alkyl)amino or —NH(C₃₋₈cycloalkyl), cyanoC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more fluoroatoms.

In one embodiment each R^(1a) is independently selected from hydrogen,C₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₁₋₄alkyl substituted withdi(C₁₋₄alkyl)amino, and C₁₋₄alkyl substituted with one or more fluoroatoms.

In one embodiment one or two R^(1a) represents hydrogen. In oneembodiment each R^(1a) represents hydrogen.

In one embodiment one or two R^(1a) represents C₁₋₄alkyl, for example—CH₃, —CH₂CH₃. In one embodiment each R^(1a) represents C₁₋₄alkyl, forexample —CH₃.

In one embodiment one or two R^(1a) represents hydroxyC₁₋₄alkyl, forexample —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH.

In one embodiment one or two R^(1a) represents C₁₋₄alkyl substitutedwith di(C₁₋₄alkyl)amino, for example —CH₂N(CH₃)₂. In one embodiment oneor two R^(1a) represents C₁₋₄alkyl substituted with one or more fluoroatoms, for example —CF₃.

In one embodiment:

(i) one R^(1a) represents hydrogen and the other R^(1a) representsC₁₋₄alkyl, for example —CH₃, —CH₂CH₃;(ii) one R^(1a) represents hydrogen and the other R^(1a) representshydroxyC₁₋₄alkyl, for example —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH;(iii) one R^(1a) represents hydrogen and the other R^(1a) representsC₁₋₄alkyl substituted with one or more fluoro atoms, for example —CF₃;or(iv) each R^(1a) independently represents C₁₋₄alkyl, for example eachR^(1a) represents —CH₃.

In one embodiment, R¹ is methyl and R^(1a) is hydrogen or methyl.

In one embodiment each R² is independently selected from hydroxyl,halogen, cyano, C₁₋₄alkyl, C₂₋₄alkenyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,R¹³, C₁₋₄alkoxy substituted with R¹³, —C(═O)—R¹³, C₁₋₄alkyl substitutedwith NR⁷R⁸, C₁₋₄alkoxy substituted with NR⁷R⁸, —NR⁷R⁸ and —C(═O)—NR⁷R⁸;or when two R² groups are attached to adjacent carbon atoms they may betaken together to form a radical of formula —O—(C(R¹⁷)₂)_(p)—O— whereinR¹⁷ represents hydrogen or fluorine and p represents 1 or 2.

In one embodiment each R² is independently selected from halogen, cyano,C₁₋₄alkyl, C₂₋₄alkenyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl, hydroxyC₁₋₄alkoxy,haloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, R¹³, C₁₋₄alkoxy substituted withR¹³, —C(═O)—R¹³, C₁₋₄alkyl substituted with NR⁷R⁸, C₁₋₄alkoxysubstituted with NR⁷R⁸, —NR⁷R⁸ or —C(═O)—NR⁷R⁸;

In one embodiment one or more R² represents hydroxyl.

In one embodiment one or more R² represents halogen, for examplefluorine, chlorine or bromine.

In one embodiment one or more R² represents cyano.

In one embodiment one or more R² represents C₁₋₄alkyl, for example —CH₃.

In one embodiment one or more R² represents C₂₋₄alkenyl, for example—CH═CH₂.

In one embodiment one or more R² represents C₁₋₄alkoxy, for exampleCH₃O—, (CH₃)₂CHO—, CH₃CH₂O—, or CD₃O—.

In one embodiment one or more R² represents hydroxyC₁₋₄alkyl, forexample —CH₂OH.

In one embodiment one or more R² represents hydroxyC₁₋₄alkoxy, forexample —OCH₂CH₂OH.

In one embodiment one or more R² represents haloC₁₋₄alkyl, for example—CF₃.

In one embodiment one or more R² represents haloC₁₋₄alkoxy, for example—OCH₂CH₂F or —O—CHF₂—. In one embodiment one or more R² represents—OCH₂CH₂F or —O—CHF₂ or —OCF₃.

In one embodiment one or more R² represents C₁₋₄alkoxyC₁₋₄alkyl, forexample —CH₂CH₂OCH₃.

In one embodiment one or more R² represents R¹³. R¹³ may represent asaturated 5 membered monocyclic heterocyclyl containing two oxygenheteroatoms, for example dioxolanyl, particularly 2-dioxolanyl.

In one embodiment one or more R² represents C₁₋₄alkoxy substituted withR¹³. R¹³ may represent C₃₋₈cycloalkyl, for example cyclopropyl. One ormore R² may represent —OCH₂C₃H₅.

In one embodiment one or more R² represents —C(═O)—R¹³. R¹³ mayrepresent a saturated 5 membered monocyclic heterocyclyl containing onenitrogen heteroatom, for example pyrrolidinyl. R² may represent—C(═O)-(1-pyrrolidinyl).

In one embodiment one or more R² represents C₁₋₄alkyl substituted with—NR⁷R⁸. In one embodiment R⁷ and R⁸ each represent hydrogen. One or moreR² may represent —CH₂NH₂. In another embodiment R⁷ and R⁸ may eachindependently represent C₁₋₆alkyl, for example —CH₂CH₃ or —CH₃. One ormore R² may represent —CH₂N(CH₂CH₃)₂, —CH₂N(CH₃)₂ or —CH₂N(CH₂CH₃)(CH₃).

In one embodiment one or more R² represents C₁₋₄alkoxy substituted with—NR⁷R⁸. In one embodiment one of R⁷ and R⁸ represents hydrogen and theother represents C₁₋₆alkyl, for example —CH₃. One or more R² mayrepresent —OCH₂CH₂NHCH₃. In one embodiment R⁷ and R⁸ each representhydrogen. One or more R² may represent —OCH₂CH₂NH₂.

In one embodiment one or more R² represents —NR⁷R⁸. In one embodimentone of R⁷ and R⁸ represents hydrogen and the other represents C₁₋₆alkyl,for example —CH₃. In one embodiment each of R⁷ and R⁸ representsC₁₋₆alkyl, for example —CH₃.

In one embodiment one or more R² represents —C(═O)—NR⁷R⁸. In oneembodiment one of R⁷ and R⁸ represents hydrogen and the other representsC₁₋₆alkyl, for example —CH₃.

In one embodiment when two R² groups are attached to adjacent carbonatoms they may be taken together to form a radical of formula—O—(C(R¹⁷)₂)_(p)—O— wherein R¹⁷ represents hydrogen and p represents 1.

In one embodiment n is equal to 0. In one embodiment n is equal to 1. Inone embodiment n is equal to 2. In one embodiment n is equal to 3. Inone embodiment n is equal to 4.

In one embodiment n is equal to 1. R² may be at the 3-position. R² mayrepresent

(i) haloC₁₋₄alkoxy, for example —O—CHF₂;(ii) C₁₋₄alkoxy, for example CH₃OO— or (CH₃)₂CHO—;(iii) cyano; or(iv) —NR⁷R⁸, for example —NHCH₃.

In one embodiment n is equal to 1. R² may be at the 3-position. R² mayrepresent haloC₁₋₄alkoxy, for example —OCF₃.

In one embodiment n is equal to 1. R² may be at the 3-position. R² mayrepresent C₁₋₄alkoxy, for example CH₃O—. In one embodiment n is equalto 1. R² may be at the 3-position. R² may represent —NR⁷R⁸ where R⁷ andR⁸ each independently represent C₁₋₆alkyl, for example —N(CH₃)₂.

In one embodiment n is equal to 2. One R² may be at the 3-position andthe other may be at the 5-position:

(i) each R² may represent C₁₋₄alkoxy, for example each R² may be CH₃O—,or the R² at the 3-position may be (CH₃)₂CHO— and the R² at the5-position may be CH₃O—, or the R² at the 3-position may be CH₃O— andthe R² at the 5-position may be CD₃O—;(ii) the R² at the 3-position may represent halogen, for examplefluorine, chlorine or bromine, and the R² at the 5-position mayrepresent C₁₋₄alkoxy, for example CH₃O—, CD₃O— or CH₃CH₂O—;(iii) the R² at the 3-position may represent C₁₋₄alkyl, for example—CH₃, and the R² at the 5-position may represent C₁₋₄alkoxy, for exampleCH₃O—;(iv) the R² at the 3-position may represent cyano, and the R² at the5-position may represent C₁₋₄alkoxy, for example CH₃O—;(v) the R² at the 3-position may represent C₁₋₄alkyl substituted withNR⁷R⁸, for example —CH₂NH₂ or —CH₂N(CH₃)₂ or —CH₂N(CH₂CH₃)₂ or—CH₂N(CH₂CH₃)(CH₃), and the R² at the 5-position may representC₁₋₄alkoxy, for example CH₃O—;(vi) the R² at the 3-position may represent C₁₋₄alkoxy, for exampleCH₃O—, and the R² at the 5-position may represent —C(═O)—NR⁷R⁸, forexample —C(═O)NHCH₃ or —C(═O)NH₂;(vii) the R² at the 3-position may represent hydroxyC₁₋₄alkoxy, forexample —OCH₂CH₂OH, and the R² at the 5-position may representC₁₋₄alkoxy, for example CH₃O-(viii) the R² at the 3-position mayrepresent —C(═O)—R¹³, for example —C(═O)-(pyrrolidin-1-yl), and the R²at the 5-position may represent C₁₋₄alkoxy, for example CH₃O—;(ix) the R² at the 3-position may represent C₁₋₄alkoxy substituted withR¹³, for example —OCH₂C₃H₅, and the R² at the 5-position may representC₁₋₄alkoxy, for example CH₃O—;(x) the R² at the 3-position may represent C₁₋₄alkoxy, for exampleCH₃O—, and the R² at the 5-position may represent C₁₋₄alkoxy substitutedwith NR⁷R⁸, for example —OCH₂CH₂NHCH₃ or —OCH₂CH₂NH₂;(xi) the R² at the 3-position may represent C₁₋₄alkoxy, for exampleCH₃O—, and the R² at the 5-position may represent C₂₋₄alkenyl, forexample —CH═CH₂;(xii) the R² at the 3-position may represent C₁₋₄alkoxy, for exampleCH₃O—, and the R² at the 5-position may represent C₁₋₄alkoxyC₁₋₄alkyl,for example —CH₂CH₂OCH₃; or the R² at the 3-position may be CH₃O— andthe R² at the 5-position may be CH₃OCH₂—;(xiii) the R² at the 3-position may represent R¹³, for example2-dioxolanyl, and the R² at the 5-position may represent C₁₋₄alkoxy, forexample CH₃O—;(xiv) the R² at the 3-position may represent hydroxyC₁₋₄alkoxy, forexample —OCH₂CH₂OH, and the R² at the 5-position may represent halogen,for example fluorine;(xv) the R² at the 3-position may represent haloC₁₋₄alkoxy, for example—OCH₂CH₂F, and the R² at the 5-position may represent C₁₋₄alkoxy, forexample CH₃O—;(xvi) the R² at the 3-position may represent halogen, for examplefluorine, and the R² at the 5-position may represent —C(═O)—NR⁷R⁸, forexample —C(═O)NHCH₃;(xvii) the R² at the 3-position may represent C₁₋₄alkoxy, for exampleCH₃O—, and the R² at the 5-position may represent halogen, for examplefluorine; or(xviii) the R² at the 3-position may represent representshydroxyC₁₋₆alkyl, for example —CH₂OH, and the R² at the 5-position mayrepresent C₁₋₄alkoxy, for example CH₃O—.

In one embodiment n is equal to 2. One R² may be at the 3-position andthe other may be at the 5-position:

(i) the R² at the 3-position may represent hydroxyl and the R² at the5-position may represent C₁₋₄alkoxy, for example CH₃O—;(ii) each R² may represent halogen, for example chlorine;(iii) the R² at the 3-position may represent C₁₋₄alkoxy, for exampleCH₃O— and the R² at the 5-position may represent C₁₋₄alkyl substitutedwith —NR⁷R⁸ where R⁷ and R⁸ may each independently represent C₁₋₆alkyl,for example —CH₂N(CH₂CH₃)₂;(iv) the R² at the 3-position may represent C₁₋₄alkoxy, for exampleCH₃O—, and the R² at the 5-position may represent haloC₁₋₄alkoxy, forexample —OCHF₂;(v) the R² at the 3-position may represent C₁₋₄alkoxy, for exampleCH₃O—, and the R² at the 5-position may represent haloC₁₋₄alkyl, forexample —CHF₂; or(vi) each R² may represent hydroxyl.

In one embodiment n is equal to 2. One R² may be at the 3-position andthe other may be at the 5-position. Each R² may represent C₁₋₄alkoxy,for example each R² may be CH₃O—, (CH₃)₂CHO—, CH₃CH₂O—, CD₃O—. In oneembodiment both R² are for example CH₃O—, or CD₃O—. In one embodimentboth R² are CH₃O—.

In one embodiment n is equal to 2. One R² may be at the 4-position andthe other may be at the 5-position. Each R² may represent C₁₋₄alkoxy,for example each R² may be CH₃O—.

In one embodiment n is equal to 2. One R² may be at the 5-position andthe other may be at the 6-position. Each R² may represent C₁₋₄alkoxy,for example each R² may be CH₃O—.

In one embodiment n is equal to 2. One R² may be at the 2-position andthe other may be at the 5-position:

(i) each R² may represent C₁₋₄alkoxy, for example each R² may be CH₃O—;or(ii) the R² at the 2-position may be halogen, for example chlorine, andthe R² at the 5 position may represent C₁₋₄alkoxy, for example CH₃O—.

In one embodiment n is equal to 3. One R² may be at the 2-position, onemay be at the 3-position and one may be at the 5-position:

(i) the R² at the 2-position may represent halogen, for examplechlorine, the R² at the 3-position and the 5-position may each representC₁₋₄alkoxy, for example each of these R² may be CH₃O—; or(ii) the R² at the 2-position may represent C₁₋₄alkyl, for example —CH₃,the R² at the 3-position and the 5-position may each representC₁₋₄alkoxy, for example each of these R² may be CH₃O—.

In one embodiment n is equal to 3. One R² may be at the 3-position, onemay be at the 4-position and one may be at the 5-position:

(i) the R² at the 3-position may represent C₁₋₄alkoxy, for exampleCH₃O—, the R² at the 4-position and the 5-position may each representhalogen, for example fluorine; or;(ii) the R² at the 3-position may represent C₁₋₄alkoxy, for exampleCH₃O—, the R² at the 4-position and the 5-position may be taken togetherto form a radical of formula —O—(C(R¹⁷)₂)_(p)—O— wherein R¹⁷ representshydrogen and p represents 1.

In one embodiment n is equal to 3. One R² may be at the 2-position, onemay be at the 3-position and one may be at the 5-position: (i) the R² atthe 2-position may represent halogen, for example fluorine, the R² atthe 3-position and the 5-position may each represent C₁₋₄alkoxy, forexample CH₃O—.

In one embodiment n is equal to 4. One R² may be at the 2-position, onemay be at the 3-position, one may be at the 5-position and one may be atthe 6-position, the R² at the 2-position and the 6-position may eachrepresent halogen, for example chlorine or fluorine, the R² at the3-position and the 5-position may each represent C₁₋₄alkoxy, for exampleCH₃O—.

R³ may represent C₁₋₆alkyl, hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,hydroxyC₂₋₆alkynyl, haloC₁₋₆alkyl, haloC₁₋₆alkyl optionally substituted(e.g. substituted) with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups or with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkylsubstituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with oneor two halogens and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, C₁₋₆alkylsubstituted with carboxyl, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NR¹²—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with R⁹ and optionallysubstituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with hydroxyland R⁹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —C(═O)—R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, hydroxyC₁₋₆alkoxy,C₂₋₆alkenyl, C₂₋₆alkynyl, R¹³, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)— or C₁₋₆alkyl substituted with—P(═O)(OC₁₋₆alkyl)₂.

R³ may represent C₁₋₆alkyl, hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, C₁₋₆alkyl substituted with R⁹,C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted with hydroxyland —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogens and—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with carboxyl,C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with hydroxyl and R⁹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹²,C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with—C(═O)—R⁹, C₂₋₆alkynyl substituted with R⁹, hydroxyC₁₋₆alkoxy,C₂₋₆alkenyl, C₂₋₆alkynyl, R¹³ or C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—.

In one embodiment R³ represents C₁₋₆alkyl. R³ may represent —CH₃,—CH₂CH₃, —CH₂CH₂CH₃ or —CH₂CH(CH₃)₂.

In one embodiment R³ represents hydroxyC₁₋₆alkyl. R³ may represent—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CHOHCH₃, —CH₂CHOHCH₂CH₃, —CH₂CHOHCH(CH₃)₂,—CH₂CH₂C(OH)(CH₃)₂, —CH₂CHOHCH₂OH or —CH₂C(CH₃)₂OH. R³ may represent—CD₂CD₂OH or —CD₂CD₂CD₂OH. R³ may represent —CH(CH₃)CH₂OH.

In one embodiment R³ represents haloC₁₋₆alkyl. R³ may represent—CH₂CH₂CH₂Cl or —CH₂CH₂CH₂CH₂Cl. R³ may represent —CH₂CH₂F or —CH₂CH₂I.

In one embodiment R³ represents haloC₁₋₆alkyl optionally substitutedwith —O—C(═O)—C₁₋₆alkyl. R³ may represent —CH₂CH(CF₃)—O—C(═O)CH₃.

In one embodiment R³ represents hydroxyhaloC₁₋₆alkyl, for example R³ mayrepresent —CH₂CHOHCF₃.

In one embodiment R³ represents hydroxyC₂₋₆alkynyl, for example R³ mayrepresent —CH₂—C≡C—CH₂OH or —CH₂—C≡C—C(CH₃)₂OH.

In one embodiment R³ represents C₁₋₆alkyl substituted with—C(═O)—C₁₋₆alkyl, for example R³ may represent CH₃—C(═O)—CH₂—,(CH₃)₂CH—C(═O)—CH₂I.

In one embodiment R³ represents C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groups.R³ may represent —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃ or —CH₂CHOHCH₂OCH₃.

In one embodiment R³ represents C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groupsor with —O—C(═O)—C₁₋₆alkyl. R³ may represent —CH₂CH(—O—C(═O)CH₃)CH₂OCH₃.

In one embodiment R³ represents C₁₋₆alkyl substituted with R⁹.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents optionally substituted C₃₋₈cycloalkyl, for examplecyclopropyl or cyclopentyl. R³ may represent —CH₂—C₃H₅ or —CH₂C₅H₉.

In one embodiment where the C₃₋₈cycloalkyl is cyclopropyl it issubstituted by one hydroxyC₁₋₄alkyl, for example —CH₂OH.

In one embodiment where the C₃₋₈cycloalkyl is cyclopropyl it issubstituted by one 6-membered aromatic monocyclic heterocyclylcontaining one nitrogen heteroatom, for example 4-pyridinyl.

In another embodiment where the C₃₋₈cycloalkyl is cyclopropyl it issubstituted by one Cl₁₋₆alkyl-O—C(═O)—, for example CH₃CH₂—O—C(═O)—.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents an optionally substituted aromatic 5 membered monocyclicheterocyclyl containing a nitrogen and an oxygen heteroatom, for exampleisoxazolyl. In one embodiment the heterocyclyl is substituted with oneor two C₁₋₄alkyl groups, for example —CH₃ groups. R³ may representmethyl substituted with 5-isoxazoyl substituted in the 3 position with—CH₃ or methyl substituted with 3-isoxazoyl substituted in the 5position with —CH₃.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents an optionally substituted saturated 6 membered monocyclicheterocyclyl containing a nitrogen and an oxygen heteroatom, for examplemorpholinyl. R³ may represent ethyl or propyl substituted by4-morpholinyl. R³ may represent methyl substituted by 3-morpholinyl. R³may represent methyl substituted by 6-morpholinyl.

In one embodiment the heterocyclyl is substituted with one or twoC₁₋₄alkyl groups, for example —CH₃ groups. R³ may represent ethyl orpropyl substituted by 4-morpholinyl substituted in the 2 and 6 positionsby —CH₃. R³ may represent methyl substituted by 3-morpholinylsubstituted in the 5 position by two —CH₃. R³ may represent methylsubstituted by 6-morpholinyl substituted in the 4 position by —CH(CH₃)₂.In one embodiment the heterocyclyl is substituted with one C₁₋₄alkylgroup, for example —CH(CH₃)₂, and one ═O. R³ may represent methylsubstituted by 6-morpholinyl substituted in the 3 position by ═O and 4position by —CH(CH₃)₂.

In another embodiment the heterocyclyl is substituted withphenylC₁₋₆alkyl, wherein the phenyl is optionally substituted with R¹⁶,for example —CH₂—C₆H₅. R³ may represent methyl substituted by2-morpholinyl substituted in the 4 position by —CH₂—C₆H₅.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents a saturated or an aromatic 3, 4, 5 or 6 membered monocyclicheterocyclyl containing one or two oxygen heteroatoms, for exampleethylene oxide (oxiranyl), trimethylene oxide (oxetanyl),tetrahydrofuranyl, dioxolanyl, tetrahydropyranyl or furanyl. R³ may bemethyl substituted with 2-tetrahydrofuranyl, 2-dioxolane, ethyleneoxide, 2-furanyl or 4-tetrahydropyranyl,

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents an optionally substituted 4 membered heterocyclyl containingone oxygen heteroatom, for example oxetanyl, and the heterocyclyl issubstituted with one C₁₋₄alkyl group, for example —CH₃. R³ may be methylsubstituted with 3-oxetanyl substituted in the 3 position by —CH₃.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents an optionally substituted 4 membered heterocyclyl containingone oxygen heteroatom, for example oxetanyl, and the heterocyclyl issubstituted with one C₁₋₄alkyl substituted with —NR¹⁴R¹⁵ group where oneof R¹⁴ and R¹⁵ is hydrogen and the other is C₁₋₄alkyl, for example—CH(CH₃)₂. R³ may be methyl substituted with 3-oxetanyl substituted inthe 3 position by —CH₂NHCH(CH₃)₂.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents an optionally substituted aromatic 6 membered monocyclicheterocycle containing one or two nitrogen heteroatoms, for examplepyridinyl or pyrazinyl. R³ may represent methyl substituted with3-pyridinyl or 2-pyrazinyl. R³ may represent propyl substituted with4-pyridinyl.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents an optionally substituted aromatic 6 membered monocyclicheterocycle containing two nitrogen heteroatoms, for examplepyrimidinyl. R³ may represent methyl or propyl substituted with2-pyrimidinyl.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents an optionally substituted aromatic 6 membered monocyclicheterocyclyl containing one nitrogen heteroatom, for example pyridinyl,substituted with one halogen, for example chlorine or bromine. R³ mayrepresent methyl substituted with 3-pyridinyl substituted in the 6position by chlorine or 2-pyridinyl substituted in the 6 position bybromine.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents an optionally substituted aromatic 6 membered monocyclicheterocyclyl containing one nitrogen heteroatom, for example pyridinyl,substituted with:

(i) one C₁₋₄alkyl, for example —CH₃. R³ may represent propyl substitutedwith 6-pyridinyl substituted in the 4 position by —CH₃; or(ii) one C₁₋₄alkoxy, for example —OCH₃. R³ may represent propylsubstituted with 2-pyridinyl substituted in the 3 position by —OCH₃. R³may represent methyl substituted with 2-pyridinyl substituted in the 6position by —OCH₃;(iii) one C₁₋₄alkyl substituted by —NR¹⁴R¹⁵. In one embodiment R¹⁴ andR¹⁵ each represent hydrogen. R³ may represent methyl substituted with6-pyridinyl substituted in the 2 position by —CH₂NH₂; or(iv) one —NR¹⁴R¹⁵. In one embodiment one of R¹⁴ and R¹⁵ representshydrogen and the other represents C₁₋₄alkyl, for example —CH₃. R³ mayrepresent methyl substituted with 6-pyridinyl substituted in the 2position by —NHCH₃.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents an optionally substituted aromatic 6 membered monocyclicheterocyclyl containing two nitrogen heteroatoms, for examplepyrimidinyl, substituted with:

(i) one or two C₁₋₄alkoxy groups, for example —OCH₃. R³ may representpropyl substituted with 2-pyrimidinyl substituted in the 4 position by—OCH₃. R³ may represent methyl substituted with 2-pyrimidinylsubstituted in the 4 and 6 positions by —OCH₃;(ii) one hydroxyl group, for example —OH. R³ may represent propylsubstituted with 2-pyrimidinyl substituted in the 4 position by —OH.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents an optionally substituted saturated 6 membered monocyclicheterocyclyl containing two nitrogen heteroatoms, for examplepiperazinyl. R³ may represent methyl substituted with 3-piperazinyl.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents an optionally substituted saturated 6 membered monocyclicheterocyclyl containing two nitrogen heteroatoms, for examplepiperazinyl substituted with R¹³, for example said R¹³ representingpiperidinyl being substituted with one C₁₋₄alkyl-C(═O)—, for example—C(═O)—CH₃. R³ may represent ethyl substituted with 1-piperazinylsubstituted in the 4 position with 4-piperidinyl substituted in the 1position with —C(═O)—CH₃.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents an optionally substituted saturated 6 membered monocyclicheterocyclyl containing two nitrogen heteroatoms, for examplepiperazinyl substituted with C₁₋₄alkyl substituted with —C(═O)—NR¹⁴R¹⁵.R³ may represent ethyl substituted with 1-piperazinyl substituted in the4 position with —CH₂C(═O)NHCH(CH₃)₂.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents a partially saturated 6 membered monocyclic heterocyclylcontaining one nitrogen heteroatom which may optionally be substituted.R³ may represent ethyl or propyl substituted with1,2,3,6-tetrahydropyridine.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents an optionally substituted saturated 4 membered monocyclicheterocyclyl containing one nitrogen heteroatom, for example azetidinyl.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents a saturated 4 membered monocyclic heterocyclyl containingone nitrogen heteroatom, for example azetidinyl, and the heterocyclyl issubstituted with one or two halogens, for example fluorine. R³ mayrepresent propyl substituted by 1-azetidinyl substituted in the 3position by two fluorines. In another embodiment when R³ representsC₁₋₆alkyl substituted with R⁹, R⁹ represents a saturated 4 memberedmonocyclic heterocyclyl containing one nitrogen heteroatom, for exampleazetidinyl, and the heterocyclyl is substituted with one hydroxyl group.R³ may represent propyl substituted by 1-azetidinyl substituted in the 3position by one —OH.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents a saturated 5 membered monocyclic heterocyclyl containingone nitrogen heteroatom, for example pyrrolidinyl. R³ may representethyl or propyl substituted with 1-pyrrolidinyl or 2-pyrrolidinyl.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents a saturated 5 membered monocyclic heterocyclyl containingone nitrogen heteroatom, for example pyrrolidinyl, and the heterocyclylis substituted. For example the heterocyclyl is substituted with:

a) one or two halogens, for example fluorine. R³ may represent propylsubstituted with 1-pyrrolidinyl substituted in the 3 position by twofluorines or with 1-pyrrolidinyl substituted in the 3 position by onefluorine;b) one haloC₁₋₄alkyl, for example —CH₂Cl. R³ may represent propylsubstituted with 1-pyrrolidinyl substituted in the 2 position by —CH₂Cl;c) one hydroxyl group. R³ may represent ethyl or propyl substituted with1-pyrrolidinyl substituted in the 3 position by —OH;d) one ═O group. R³ may represent ethyl or propyl substituted with1-pyrrolidinyl substituted in the 2 position by ═O;e) one —S(═O)₂—C₁₋₄alkyl group and the C₁₋₄alkyl may be —CH₃. R³ mayrepresent propyl substituted with 1-pyrrolidinyl substituted in the 3position by —S(═O)₂—CH₃;f) one —NR¹⁴R¹⁵ group. In one embodiment R¹⁴ and R¹⁵ each representhydrogen. R³ may represent ethyl or propyl substituted with1-pyrrolidinyl substituted in the 3 position with —NH₂. In anotherembodiment R¹⁴ and R¹⁵ each independently represent C₁₋₄alkyl optionallysubstituted with hydroxyl, for example —CH₃. R³ may represent ethylsubstituted with 1-pyrrolidinyl substituted in the 3 position with—N(CH₃)₂. In another embodiment one of R¹⁴ and R¹⁵ is hydrogen and theother is C₁₋₄alkyl optionally substituted with hydroxyl, for example—CH₃. R³ may represent propyl substituted with 1-pyrrolidinylsubstituted in the 3 position with —NHCH₃;g) one or two C₁₋₄alkyl groups, for example —CH₃ or —CH(CH₃)₂. R³ mayrepresent ethyl or propyl substituted with 1-pyrrolidinyl substituted inthe 2 position with —CH₃, 1-pyrrolidinyl substituted in the 2 and the 5position with —CH₃ or 1-pyrrolidinyl substituted in the 2 position withtwo —CH₃;h) one carboxyl group. R³ may represent ethyl substituted with1-pyrrolidinyl substituted in the 2 position with —C(═O)OH;i) one hydroxyC₁₋₄alkyl, for example —CH₂OH, —C(CH₃)₂OH or —CH₂CH₂OH. R³may represent ethyl or propyl substituted with 1-pyrrolidinylsubstituted in the 2 position with —CH₂OH;j) R¹³. In one embodiment R¹³ represents a saturated 6-memberedmonocyclic heterocyclyl containing one nitrogen heteroatom. In anotherembodiment R¹³ represents a saturated 6-membered monocyclic heterocyclylcontaining one nitrogen and one oxygen heteroatom. In a furtherembodiment R¹³ represents a saturated 6-membered monocyclic heterocyclylcontaining one nitrogen and one oxygen heteroatom, and the heterocyclylis substituted, for example substituted with two C₁₋₆alkyl groups, forexample two —CH₃ groups. R³ may represent propyl substituted with1-pyrrolidinyl substituted in the 3 position by 1-piperidinyl, or propylsubstituted with 1-pyrrolidinyl substituted in the 3 position by4-morpholinyl substituted in positions 2 and 6 by —CH₃;k) one cyano group. R³ may represent ethyl or propyl substituted with1-pyrrolidinyl substituted in the 3 position by —CN;l) one cyanoC₁₋₄alkyl, for example —CH₂CN. R³ may represent propylsubstituted with 1-pyrrolidinyl substituted in the 2 position by—CH₂CN.R³ may represent ethyl substituted with 1-pyrrolidinylsubstituted in the 2 position by —CH₂CN;m) one C₁₋₄alkyl substituted with —NH—S(═O)₂-haloC₁₋₄alkyl, for example—CH₂NH—S(═O)₂—CF₃. R³ may represent propyl substituted with1-pyrrolidinyl substituted in the 2 position by —CH₂NH—S(═O)₂—CF₃; orn) one C₁₋₆alkyl-O—C(═O)—, for example (CH₃)₃C—O—C(═O)— or CH₃—O—C(═O)—.R³ may represent methyl or ethyl substituted by 2-pyrrolidinylsubstituted in the 1 position by (CH₃)₃C—O—C(═O)— or substituted by1-pyrrolidinyl substituted in the 2 position by CH₃—O—C(═O)—.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents a saturated 5 membered monocyclic heterocyclyl containingone nitrogen heteroatom, for example pyrrolidinyl, and the heterocyclylis substituted. For example the heterocyclyl is substituted with a6-membered aromatic monocyclic heterocyclyl containing one or twonitrogen heteroatoms, for example pyridinyl or pyrimidinyl, andoptionally substituted with R¹⁶. In one embodiment R¹⁶ representsC₁₋₄alkoxy, for example —OCH₃. R³ may represent methyl substituted by3-pyrrolidinyl substituted in the 1-position by 2-pyridinyl substitutedin the 3-position by —OCH₃. R³ may represent methyl substituted by3-pyrrolidinyl substituted in the 1-position by 2-pyrimidinylsubstituted in the 4-position by —OCH₃.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents a saturated 6 membered monocyclic heterocyclyl containingone nitrogen heteroatom, for example piperidinyl. R³ may representmethyl, ethyl or propyl substituted by 4-piperidinyl or 1-piperidinyl.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents a saturated 6 membered monocyclic heterocyclyl containingone nitrogen heteroatom, for example piperidinyl, and the heterocyclylis substituted. For example the heterocyclyl is substituted with:

a) one or two halogens, for example fluorine. R³ may represent ethylsubstituted by 1-piperidinyl substituted at the 4 position by twofluorines;b) one hydroxyl group. R³ may represent methyl or ethyl substituted by1-piperidinyl substituted at the 4 position by one —OH or 4-piperidinylsubstituted at the 4 position by one —OH;c) one —NR¹⁴R¹⁵ group. In one embodiment R¹⁴ and R¹⁵ each representhydrogen. R³ may represent ethyl substituted by 1-piperidinylsubstituted at the 3 position or the 4 position by —NH₂. In anotherembodiment R¹⁴ and R¹⁵ each independently represent C₁₋₄alkyl optionallysubstituted with hydroxyl, for example —CH₃. R³ may represent ethylsubstituted by 1-piperidinyl substituted at the 4 position by —N(CH₃)₂;d) one or two C₁₋₄alkyl groups, for example —CH₃ or —CH(CH₃)₂. R³ mayrepresent methyl, ethyl or propyl substituted by 1-piperidinylsubstituted at the 2 position by —CH₃, 1-piperidinyl substituted at the2 and the 6 position by —CH₃, 4-piperidinyl substituted at the 1position by —CH(CH₃)₂, 4-piperidinyl substituted at the 1 position by—CH₃, 1-piperidinyl substituted at the 3 and the 5 position by —CH₃;e) one hydroxyC₁₋₄alkyl, for example —CH₂OH, —C(CH₃)₂OH or —CH₂CH₂OH. R³may represent ethyl substituted by 1-piperidinyl substituted in the 4position by —C(CH₃)₂OH, 1-piperidinyl substituted in the 4 position by—CH₂CH₂OH; 1-piperidinyl substituted in the 4 position by —CH₂OH;f) one cyano group. R³ may represent ethyl or propyl substituted with1-piperidinyl substituted at the 3 position with —CN;g) one C₁₋₆alkyl-O—C(═O)—, for example CH₃CH₂—O—C(═O)—, (CH₃)₃C—O—C(═O)—or CH₃—O—C(═O)—. R³ may represent methyl or ethyl substituted with1-piperidinyl substituted in the 4 position by CH₃CH₂—O—C(═O)—,4-piperidinyl substituted in the 1 position by (CH₃)₃C—O—C(═O)—;h) one C₁₋₆alkyl-O—C(═O)—, for example (CH₃)₃C—O—C(═O)—, and onehydroxyl group. R³ may represent methyl substituted with 4-piperidinylsubstituted in the 4 position by —OH and in the 1 position by(CH₃)₃C—O—C(═O)—;i) one C₁₋₆alkyl-O—C(═O)—, for example (CH₃)₃C—O—C(═O)—, and oneC₁₋₄alkoxy group, for example —OCH₃. R³ may represent methyl substitutedwith 4-piperidinyl substituted in the 4 position by —OCH₃ and in the 1position by (CH₃)₃C—O—C(═O)—;j) one C₁₋₄alkoxy group, for example —OCH₃. R³ may represent methyl orethyl substituted with 1-piperidinyl substituted in the 4 position by—OCH₃ or 4-piperidinyl substituted in the 4 position by —OCH₃;k) one haloC₁₋₄alkyl group, for example —CF₃. R³ may represent propylsubstituted with 1-piperidinyl substituted in the 4 position by —CF₃; orl) one —C(═O)—NR¹⁴R¹⁵ where R¹⁴ and R¹⁵ both represent hydrogen. R³ mayrepresent ethyl substituted with 1-piperidinyl substituted in the 3position by —C(═O)—NH₂. R³ may represent ethyl or propyl substitutedwith 1-piperidinyl substituted in the 2 position by —C(═O)—NH₂.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents a saturated 6 membered monocyclic heterocyclyl containingone nitrogen heteroatom, for example piperidinyl, and the heterocyclylis substituted. For example the heterocyclyl is substituted with:

a) one ═O. R³ may represent ethyl substituted by 1-piperidinylsubstituted at the 4 position by ═O, or propyl substituted by1-piperidinyl substituted at the 2 position by ═O;b) one C₁₋₆alkyl substituted with —NR¹⁴R¹⁵ where R¹⁴ and R¹⁵ bothrepresent hydrogen. R³ may represent ethyl substituted with1-piperidinyl substituted in the 4 position by —CH₂NH₂.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents a saturated 6 membered monocyclic heterocyclyl containingone nitrogen heteroatom, for example piperidinyl, and the heterocyclylis substituted. For example the heterocyclyl is substituted with a6-membered aromatic monocyclic heterocyclyl containing two nitrogenheteroatoms, for example pyrimidinyl, and optionally substituted withR¹⁶. In one embodiment R¹⁶ represents C₁₋₄alkoxy, for example —OCH₃. R³may represent methyl substituted by 4-piperidinyl substituted in the1-position by 2-pyrimidinyl substituted in the 4-position by —OCH₃.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents a bicyclic heterocyclyl containing a benzene ring fused toa 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms. In oneembodiment the bicyclic heterocyclyl contains a benzene ring fused to a5-membered ring containing 1 ring heteroatom. In one embodiment the ringheteroatom is a nitrogen heteroatom. In one embodiment the bicyclicheterocyclyl is substituted with two ═O groups on the 5-membered ringcontaining one ring heteroatom. R³ may represent ethyl, propyl or butylsubstituted with isoindolyl-1,3,-dione (e.g. isoindol-2-yl-1,3-dione,also known as phtalimidyl). R³ may represent —CH(CH₃)CH₂— substitutedwith isoindolyl-1,3,-dione.

In one embodiment when R³ represents C₁₋₆alkyl (for example ethyl orpropyl) substituted with R⁹, R⁹ represents an optionally substitutedmonocyclic heterocycl containing at least one heteroatom selected fromN, O or S. In one embodiment R⁹ represents a 4, 5 or 6 memberedmonocyclic saturated heterocycle substituted with two substituents whichare attached to the same atom and which are taken together to form a 4to 7-membered saturated monocyclic heterocyclyl containing at least oneheteroatom selected from N, O or S; and R³ represents C₁₋₆alkyl (forexample ethyl or propyl) substituted with a 4, 5 or 6 memberedmonocyclic saturated heterocycle substituted with two substituents whichare attached to the same atom and which are taken together to form a 4to 7-membered saturated monocyclic heterocyclyl containing at least oneheteroatom selected from N, O or S. For example R³ may represent ethylsubstituted with 2-oxa-6-aza-spiro[3.3]heptane or R³ may represent ethylsubstituted with 1-piperidinyl substituted on the 4 position by1,4-dioxolane e.g. to form 1,4-dioxa-8-aza-spiro[4.5]decane.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents an optionally substituted aromatic 5 membered monocyclicheterocyclyl containing one sulphur heteroatom, for example thiophene.R³ may represent methyl substituted with 2-thiophenyl. In one embodimentthe aromatic 5 membered monocyclic heterocyclyl containing one sulphurheteroatom is substituted with one chlorine. R³ may represent methylsubstituted with 2-thiophenyl substituted at the 5 position by chlorine.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents an optionally substituted aromatic 5 membered monocyclicheterocyclyl containing one sulphur and one nitrogen heteroatom, forexample thiazole. The 5-membered heterocyclyl may be substituted withfor example one C₁₋₄alkyl, for example —CH₃. R³ may represent methylsubstituted with 4-thiazolyl substituted in the 2 position by —CH₃.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents a saturated 6 membered monocyclic heterocyclyl containingtwo nitrogen heteroatoms, for example piperazinyl. R³ may representethyl or propyl substituted with 1-piperazinyl. In one embodiment whenR³ represents C₁₋₆alkyl substituted with R⁹, R⁹ represents a saturated 6membered monocyclic heterocyclyl containing two nitrogen heteroatoms,for example piperazinyl, and the heterocyclyl is substituted. Forexample the heterocyclyl is substituted with:

a) one C₁₋₄alkyl-C(═O)—, for example CH₃—C(═O)—. R³ may represent ethylsubstituted with 1-piperazinyl substituted in the 4 position byCH₃—C(═O)—;b) one hydroxyC₁₋₄alkyl, for example —CH₂CH₂OH. R³ may represent ethylsubstituted with 1-piperazinyl substituted in the 4 position by—CH₂CH₂OH;c) one or two C₁₋₄alkyl, for example —CH₃. R³ may represent ethyl orpropyl substituted with 1-piperazinyl substituted at the 3 and 5positions by —CH₃ or 1-piperazinyl substituted at the 4 position by—CH₃;d) one ═O. R³ may represent ethyl substituted with 1-piperazinylsubstituted in the 3 position by ═O; ore) one —C(═O)—R¹³. R¹³ may be C₃₋₈cycloalkyl, for example cyclopropyl.R³ may represent ethyl substituted with 1-piperazinyl substituted in the4 position by —C(═O)—C₃H₅.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents a saturated 6 membered monocyclic heterocyclyl containing twonitrogen heteroatoms, for example piperazinyl, and the heterocyclyl issubstituted. For example the heterocyclyl is substituted with twophenylC₁₋₆alkyl groups wherein the phenyl is substituted with R¹⁶. R¹⁶may represent C₁₋₄alkoxy, for example CH₃O—. R³ may represent methylsubstituted with 2-piperazinyl substituted in the 1 and 4 position bymethylphenyl wherein the phenyl is substituted in the 4 position byCH₃O—.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents an aromatic 5 membered monocyclic heterocyclyl containingfour nitrogen heteroatoms, for example tetrazolyl. R³ may representethyl substituted with 5-tetrazolyl.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents an aromatic 5 membered monocyclic heterocyclyl containingone oxygen and two nitrogen heteroatoms, for example 1,3,4-oxadiazolyl.The heterocyclyl may be substituted. For example the heterocyclyl may besubstituted with one —NR¹⁴R¹⁵ group, where each of R¹⁴ and R¹⁵ ishydrogen. Alternatively one of R¹⁴ and R¹⁵ may be hydrogen and the othermay represent C₁₋₄alkyl optionally substituted with hydroxyl, forexample —CH₂CH₂OH. R³ may represent methyl substituted with2-(1,3,4-oxadiazolyl) substituted at the 5 position by —NH₂ or2-(1,3,4-oxadiazolyl) substituted at the 5 position by —NH—CH₂CH₂OH.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents an optionally substituted aromatic 5 membered monocyclicheterocyclyl containing two nitrogen heteroatoms, for example pyrazolylor imidazolyl. R³ may represent methyl, ethyl or propyl substituted with1-pyrazolyl or 2-imidazoyl. R³ may represent methyl substituted with3-pyrazolyl or 5-pyrazolyl. The heterocyclyl may be substituted. Forexample the heterocyclyl may be substituted with one or two C₁₋₄alkyl,for example —CH₃ or —CH₂CH₃. R³ may represent methyl, ethyl or propylsubstituted with 1-imidazolyl substituted at the 2 position by —CH₃,3-pyrazolyl substituted at the 1 and 5 positions by —CH₃, 1-imidazolylsubstituted at the 2 and 5 positions by —CH₃, 1-imidazolyl substitutedat the 2 and 4 positions by —CH₃, 2-imidazolyl substituted at the 1position by —CH₃ or 2-imidazolyl substituted at the 1 position by—CH₂CH₃. R³ may represent methyl substituted with 2-imidazolylsubstituted at the 5 position by —CH₃. R³ may represent ethylsubstituted with 1-pyrazolyl substituted at the 3 position by —CH₃. R³may represent methyl substituted with 4-pyrazolyl substituted at the 1position by —CH₃. In one embodiment when R³ represents C₁₋₆alkylsubstituted with R⁹, R⁹ represents an optionally substituted aromatic 5membered monocyclic heterocyclyl containing two nitrogen heteroatoms,for example imidazolyl. The heterocyclyl may be substituted. For examplethe heterocyclyl is substituted with one C₁₋₄alkyl, for example —CH₃,and with one —S(═O)₂—NR¹⁴R¹⁵. R¹⁴ and R¹⁵ may each represent C₁₋₄alkyl,for example —CH₃. R³ may represent methyl substituted with 2-imidazolylsubstituted in the 3 position by —S(═O)₂—N(CH₃)₂ and in the 5 positionby —CH₃.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents an optionally substituted aromatic 5 membered monocyclicheterocyclyl containing two nitrogen heteroatoms, for example pyrazolyl.The heterocyclyl may be substituted. For example the heterocyclyl issubstituted with R¹³. R¹³ may represent a saturated 6 memberedmonocyclic heterocyclyl containing one oxygen heteroatom. R³ mayrepresent methyl substituted with 5-pyrazolyl substituted in the 2position by 2-tetrahydropyran. R³ may represent methyl substituted with3-pyrazolyl substituted in the 1 position by 2-tetrahydropyran.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents an optionally substituted aromatic 5 membered monocyclicheterocyclyl containing two nitrogen heteroatoms, for exampleimidazolyl. The heterocyclyl may be substituted. For example theheterocyclyl is substituted with —S(═O)₂—NR¹⁴R¹⁵. R¹⁴ and R¹⁵ may eachrepresent C₁₋₄alkyl optionally substituted with a substituent selectedfrom hydroxyl, C₁₋₄alkoxy, amino or mono- or di(C₁₋₄alkyl)amino, forexample —CH₃. R³ may represent methyl substituted with 2-imidazoylsubstituted in the 1 position by —S(═O)₂—N(CH₃)₂.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents an optionally substituted aromatic 5 membered monocyclicheterocyclyl containing three nitrogen heteroatoms, for exampletriazolyl. R³ may represent methyl substituted with 4-(1,2,3-triazolyl.The heterocyclyl may be substituted. For example the heterocyclyl issubstituted with a) one hydroxyC₁₋₄alkyl group, for example —CH₂CH₂OH.R³ may represent methyl substituted with 4-(1,2,3-triazolyl) substitutedin the 1 position by —CH₂CH₂OH or 4-(1,2,3-triazolyl) substituted in the2 position by —CH₂OH; or

b) one C₁₋₄alkyl substituted with C₁₋₆alkyl-O—C(═O)— group, for example—CH₂—C(═O)—OCH₂CH₃. R³ may represent methyl substituted with4-(1,2,3-triazolyl) substituted in the 1 position by —CH₂—C(═O)—OCH₂CH₃.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents an optionally substituted aromatic 5 membered monocyclicheterocyclyl containing three nitrogen heteroatoms, for exampletriazolyl. R³ may represent ethyl substituted with 1-(1,2,4-triazolyl.The heterocyclyl may be substituted. For example the heterocyclyl issubstituted with one C₁₋₄alkyl group, for example —CH₃. R³ may representethyl or propyl substituted with 1-(1,2,4-triazolyl) substituted in the3 position by —CH₃. R³ may represent ethyl or propyl substituted with2-(1,2,4-triazolyl) substituted in the 3 position by —CH₃.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents a saturated 5 membered monocyclic heterocyclyl containingone nitrogen and one oxygen heteroatom, for example oxazolidinyl. Theheterocyclyl may be substituted, for example substituted with one ═O. R³may represent ethyl or propyl substituted with 3-oxazolidinylsubstituted in the 2 position by ═O. R³ may represent methyl substitutedwith 5-oxazolidinyl substituted in the 2 position by ═O. Theheterocyclyl may be substituted, for example substituted with one ═O andone C₁₋₆alkyl. R³ may represent methyl substituted with 5-oxazolidinylsubstituted in the 2 position by ═O and in the 3 position by —CH(CH₃)₂.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents a saturated 6 membered monocyclic heterocyclyl containingone nitrogen and one sulphur heteroatom, for example thiomorpholinyl.The heterocyclyl may be substituted, for example substituted with two ═Ogroups on the sulphur heteroatom. R³ may represent propyl substitutedwith 4-thiomorpholinyl substituted in the 1 position by two ═O groups.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents a saturated 7 membered monocyclic heterocyclyl containingtwo nitrogen heteroatoms, for example homopiperazinyl. R³ may representethyl substituted with 1-homopiperazinyl.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents a saturated 7 membered monocyclic heterocyclyl containingone nitrogen and one oxygen heteroatom, for example homomorpholinyl. R³may represent ethyl substituted with homomorpholinyl.

In another embodiment when R³ represents C₁₋₆alkyl substituted with R⁹,R⁹ represents phenyl or naphthyl, in particular phenyl. R³ may represent—CH₂—C₆H₅. When R⁹ represents phenyl or naphthyl, in particular phenyl,the phenyl or naphthyl group may be substituted, for example by onechlorine. R³ may represent methyl substituted with phenyl substituted inthe 2, 3 or 4 position by chlorine.

In one embodiment R³ represents cyanoC₁₋₆alkyl, for example —CH₂CH₂CN or—CH₂CH₂CH₂CN.

In one embodiment R³ represents C₁₋₆alkyl substituted with hydroxyl,halo or —NR¹⁰R¹¹. In a further embodiment R³ represents C₁₋₆alkylsubstituted with hydroxyl or —NR¹⁰R¹¹. In a yet further embodiment R³represents C₁₋₆alkyl substituted with —NR¹⁰R¹¹.

In one embodiment R³ represents C₁₋₆alkyl substituted with hydroxyl,halo or —NR¹⁰R¹¹, wherein the C₁₋₆alkyl group is a straight chain alkylgroup e.g. 2-ethyl, n-propyl, n-butyl. In one embodiment R³ representsC₁₋₄alkyl substituted with —NR¹⁰R¹¹. In one embodiment R³ representsC₁₋₄alkyl substituted —NR¹⁰R¹¹, wherein the C₁₋₄alkyl group is astraight chain alkyl group e.g. 2-ethyl, n-propyl, n-butyl. In oneembodiment R³ represents C₁₋₄alkyl substituted with —NR¹⁰R¹¹, whereinthe C₁₋₄alkyl group is an ethyl group (—CH₂CH₂—).

In one embodiment when R³ represents C₁₋₆alkyl substituted with—NR¹⁰R¹¹, R¹⁰ and R¹¹ have the following meanings:

a) each of R¹⁰ and R¹¹ represent hydrogen. R³ may represent —CH₂CH₂NH₂,—CH₂CH₂CH₂NH₂ or —CH₂CH₂CH₂CH₂NH₂. R³ may represent —CH₂CH(CH₃)NH₂,—CH(CH₃)CH₂NH₂;b) one of R¹⁰ and R¹¹ represents hydrogen and the other representsC₁₋₆alkyl, for example —CH₃, —CH₂CH₃ or —CH(CH₃)₂. R³ may represent—CH₂CH₂NHCH₃, —CH₂CH₂CH₂NHCH₃, —CH₂CH₂NHCH₂CH₃, —CH₂CH₂NHCH(CH₃)₂,—CD₂-CD₂-NHCH(CH₃)₂ or —CH₂CH₂CH₂NHCH(CH₃)₂. R³ may represent—CH(CH₃)CH₂NHCH(CH₃)₂;c) each of R¹⁰ and R¹¹ independently represent C₁₋₆alkyl, for example—CH₂CH₃ or —CH(CH₃)₂. R³ may represent —CH₂CH₂N(CH₂CH₃)₂,—CH₂CH₂N(CH₂CH₃)(CH(CH₃)₂). Each of R¹⁰ and R¹¹ may independentlyrepresent C₁₋₆alkyl, for example —CH₃. R³ may represent —CH₂CH₂N(CH₃)₂or —CH₂CH₂N(CH₃)CH(CH₃)₂;d) one of R¹⁰ and R¹¹ represents hydrogen and the other representshaloC₁₋₆alkyl, for example —CH₂CF₃, —CH₂CHF₂ or —CH₂CH₂F. R³ mayrepresent —CH₂CH₂CH₂NHCH₂CF₃, —CH₂CH₂NHCH₂CHF₂ or —CH₂CH₂NHCH₂CH₂F.HaloC₁₋₆alkyl may be —C(CH₃)₂CH₂F. R³ may represent —CH(CH₃)CH₂NHCH₂CF₃,—CH₂CH(CH₃)NHCH₂CF₃, —CH₂CH₂NHCH₂CF₃,—CH₂CH₂CH₂NHCH₂CHF₂—CH₂CH₂NHCH₂CH₂CF₃, —CH₂CH₂CH₂NHCH₂CHF₂,—CH₂CH₂CH₂NHC(CH₃)₂CH₂F, —CD₂-CD₂-CD₂-NHCH₂CF₃;e) one of R¹⁰ and R¹¹ represents hydrogen and the other represents—C(═O)—C₁₋₆alkyl, for example —C(═O)-Me. R³ may represent—CH₂CH₂NH—C(═O)—CH₃;f) one of R¹⁰ and R¹¹ represents hydrogen and the other represents—S(═O)₂—C₁₋₆alkyl, for example —S(═O)₂—CH₃, —S(═O)₂—CH₂CH₃ or—S(═O)₂—CH(CH₃)₂. R³ may represent —CH₂CH₂NH—S(═O)₂—CH₃,—CH₂CH₂CH₂NH—S(═O)₂—CH₃, —CH₂CH₂NH—S(═O)₂—CH₂CH₃ or—CH₂CH₂NH—S(═O)₂—CH(CH₃)₂;g) one of R¹⁰ and R¹¹ represents hydrogen and the other represents—S(═O)₂—NR¹⁴R¹⁵, where R¹⁴ and R¹⁵ each represent C₁₋₄alkyl optionallysubstituted with hydroxyl, for example —CH₃. R³ may represent—CH₂CH₂NH—S(═O)₂—N(CH₃)₂ or —CH₂CH₂CH₂NH—S(═O)₂—N(CH₃)₂;h) one of R¹⁰ and R¹¹ represents hydrogen and the other representshydroxyC₁₋₆alkyl, for example —CH₂CH₂OH. R³ may represent—CH₂CH₂NHCH₂CH₂OH;i) one of R¹⁰ and R¹¹ represents hydrogen and the other represents—C(═O)-hydroxyhaloC₁₋₆alkyl, for example —C(═O)—C(OH)(CH₃)CF₃. R³ mayrepresent —CH₂CH₂CH₂NH—C(═O)—C(OH)(CH₃)CF₃ or—CH₂CH₂NH—C(═O)—C(OH)(CH₃)CF₃;j) one of R¹⁰ and R¹¹ represents hydrogen and the other represents—C(═O)—R⁶. R⁶ may represent C₃₋₈cycloalkyl, for example cyclopropyl. R³may represent —CH₂CH₂NH—C(═O)—C₃H₅. Alternatively, R⁶ may represent asaturated 6-membered monocyclic heterocyclyl containing one nitrogenheteroatom, for example piperidinyl. The heterocyclyl may besubstituted, for example substituted by one C₁₋₆alkyl group, for example—CH₃ to form N-methyl piperidinyl. R³ may represent—CH₂CH₂NH—C(═O)-(piperidin-3-yl) where the piperidinyl is substituted atthe 1 position by —CH₃;k) one of R¹⁰ and R¹¹ represents hydrogen and the other representscyanoC₁₋₆alkyl, for example —CH₂CH₂CN. R³ may represent—CH₂CH₂NHCH₂CH₂CNR³ may represent —CH₂CH₂CH₂NHCH₂CH₂CN;l) one of R¹⁰ and R¹¹ represents hydrogen and the other represents R⁶.R⁶ may represent C₃₋₈cycloalkyl, for example cyclopropyl or cyclopentyl,or R⁶ may represent a saturated 6-membered monocyclic heterocyclylcontaining one nitrogen heteroatom, for example piperidinyl. Theheterocyclyl may be substituted, for example substituted with fourC₁₋₆alkyl groups, for example —CH₃ to form for example2,2,6,6-tetramethyl-piperidinyl. R³ may represent —CH₂CH₂NHC₃H₅,—CH₂CH₂NHC₅H₉ or —CH₂CH₂NH-(2,2,6,6-tetramethyl-piperidin-4-yl). Forexample, the heterocyclyl may be substituted by one —S(═O)₂NR¹⁴R¹⁵, forexample —S(═O)₂NH₂. R³ may represent —CH₂CH₂NH-(piperidin-4-yl) wherethe piperidnyl is substituted in the 1 position by —S(═O)₂NH₂;m) one of R¹⁰ and R¹¹ represents hydrogen and the other representsC₁₋₆alkyl substituted with R⁶. R⁶ may represent C₃₋₈cycloalkyl, forexample cyclopropyl. R³ may represent —CH₂CH₂NHCH₂C₃H₅. Alternatively R⁶may represent a saturated, 5-membered monocyclic heterocyclyl containingone oxygen heteroatom. R³ may represent —CH₂CH₂NHCH₂—(tetrahydrofuran-2-yl). Alternatively R⁶ may represent an aromatic,6-membered monocyclic heterocyclyl containing one nitrogen heteroatom.R³ may represent —CH₂CH₂NHCH₂— (pyridin-6-yl);n) one of R¹⁰ and R¹¹ represents hydrogen and the other represents—C(═O)-haloC₁₋₆alkyl, for example —C(═O)—CF₃. R³ may represent—CH₂CH₂NHC(═O)—CF₃ or —CH₂CH₂CH₂NHC(═O)—CF₃;o) one of R¹⁰ and R¹¹ represents hydrogen and the other representsC₁₋₆alkyl substituted with —Si(CH₃)₃. R³ may represent—CH₂CH₂NHCH₂Si(CH₃)₃; orp) one of R¹⁰ and R¹¹ represents C₁₋₆alkyl and the other representsC₁₋₆alkyl substituted with R⁶. R⁶ may represent phenyl. R⁶ may representphenyl substituted with —NR¹⁴R¹⁵ where R¹⁴ and R¹⁵ each representhydrogen. In one embodiment one of R¹⁰ and R¹¹ represents —CH₃ and theother represents —CH₂—C₆H₅. R³ may represent —CH₂CH₂N(CH₃)CH₂—C₆H₅. Inone embodiment one of R¹⁰ and R¹¹ represents —CH(CH₃)₂ and the otherrepresents —CH₂—C₆H₅ wherein the phenyl is substituted in the 4-positionby —NH₂.

In one embodiment when R³ represents C₁₋₆alkyl substituted with—NR¹⁰R¹¹, R¹⁰ and R¹¹ have the following meanings:

a) one of R¹⁰ and R¹¹ represents C₁₋₆alkyl, for example —CH(CH₃)₂ andthe other represents C₁₋₆alkyl substituted with —NR¹⁴R¹⁵ where R¹⁴ andR¹⁵ each represent hydrogen. R³ may represent—CH₂CH₂N(CH(CH₃)₂)CH₂CH₂CH₂NH₂;b) one of R¹⁰ and R¹¹ represents hydrogen and the other representsC₁₋₆alkyl substituted with —C(═O)—NR¹⁴R¹⁵ where R¹⁴ and R¹⁵ eachrepresent hydrogen. R³ may represent —CH₂CH₂CH₂NHCH₂C(═O)NH₂ or—CH₂CH₂NHCH₂C(═O)NH₂;c) one of R¹⁰ and R¹¹ represents C₁₋₆alkyl, for example —CH₃ and theother represents C₁₋₆alkoxy, for example —OCH₃. R³ may represent—CH₂CH₂CH₂N(CH₃)—OCH₃.d) one of R¹⁰ and R¹¹ represents hydrogen and the other representsC₁₋₆alkoxy, for example —OCH₃. R³ may represent —CH₂CH₂NH—OCH₃; ore) one of R¹⁰ and R¹¹ represents hydrogen and the other representshydroxyhaloC₁₋₆alkyl, for example —CH₂CHOHCF₃. R³ may represent—CH₂CH₂NHCH₂CHOHCF₃.f) one of R¹⁰ and R¹¹ represents hydrogen and the other representscarboxyl (i.e.—C(═O)—OH); R³ may represent —CH₂CH₂CH₂NHCOOH.

In one embodiment R¹⁰ represents hydrogen or C₁₋₆alkyl, for examplehydrogen, —CH₃, —CH₂CH₃ or —CH(CH₃)₂. In one embodiment R¹⁰ is hydrogen.

In one embodiment R¹¹ represents hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl,—C(═O)—C₁₋₆alkyl, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, hydroxyC₁₋₆alkyl,—C(═O)-hydroxyhaloC₁₋₆alkyl, —C(═O)—R⁶, cyanoC₁₋₆alkyl, R⁶, —C(═O)—R⁶,C₁₋₆alkyl substituted with R⁶, —C(═O)-haloC₁₋₆alkyl, C₁₋₆alkylsubstituted with —Si(CH₃)₃.

In one embodiment R¹¹ represents hydrogen, —CH₃, —CH₂CH₃ or —CH(CH₃)₂,—CH₂CF₃, —CH₂CHF₂ or —CH₂CH₂F, —C(═O)—CH₃, —S(═O)₂—CH₃, —S(═O)₂—CH₂CH₃,—S(═O)₂—CH(CH₃)₂, —S(═O)₂—N(CH₃)₂, —CH₂CH₂OH, —C(═O)—C(OH)(CH₃)CF₃,—C(═O)— cyclopropyl, —CH₂CH₂CN, cyclopropyl, cyclopentyl,2,2,6,6-tetramethyl-piperidinyl, —CH₂C₃H₅, —CH₂-tetrahydrofuranyl,—C(═O)-(1-methyl-piperidin-3-yl), —C(═O)—CF₃, —CH₂Si(CH₃)₃, —CH₂—C₆H₅.

In one embodiment R³ represents —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂NHCH₃, —CH₂CH₂CH₂NHCH₃, —CH₂CH₂NHCH₂CH₃,—CH₂CH₂NHCH(CH₃)₂, —CH₂CH₂CH₂NHCH(CH₃)₂, —CH₂CH₂N(CH₂CH₃)₂,—CH₂CH₂N(CH₂CH₃)(CH(CH₃)₂), —CH₂CH₂CH₂NHCH₂CF₃, —CH₂CH₂NHCH₂CHF₂ r—CH₂CH₂NHCH₂CH₂F, —CH₂CH₂NH—C(═O)—CH₃, —CH₂CH₂NH—S(═O)₂—CH₃,—CH₂CH₂CH₂NH—S(═O)₂—CH₃, —CH₂CH₂NH—S(═O)₂—CH₂CH₃,—CH₂CH₂NH—S(═O)₂—CH(CH₃)₂, —CH₂CH₂NH—S(═O)₂—N(CH₃)₂,—CH₂CH₂CH₂NH—S(═O)₂—N(CH₃)₂, —CH₂CH₂NHCH₂CH₂OH,—CH₂CH₂CH₂NH—C(═O)—C(OH)(CH₃)CF₃, —CH₂CH₂NH—C(═O)—C(OH)(CH₃)CF₃,—CH₂CH₂NH—C(═O)—C₃H₅, —CH₂CH₂NHCH₂CH₂CN, CH₂CH₂NHC₃H₅, —CH₂CH₂NHC₅H₉,—CH₂CH₂—NHCO-(piperidin-3-yl) where the piperidin-3-yl) is substitutedin the 1 position by _—OCH₃, —CH₂CH₂NHCH₂C₃H₅,—CH₂CH₂NHCH₂(tetrahydrofuran-2-yl), —CH₂CH₂NHC(═O)—CF₃,—CH₂CH₂CH₂NHC(═O)—CF₃, —CH₂CH₂NH-(2,2,6,6-tetramethyl-piperidin-4-yl),—CH₂CH₂NHCH₂Si(CH₃)₃, —CH₂CH₂N(CH₃)CH₂—C₆H₅.

In one embodiment R³ represents C₁₋₆alkyl substituted with hydroxyl and—NR¹⁰R¹¹. In one embodiment when R³ represents C₁₋₆alkyl substitutedwith hydroxyl and —NR¹⁰R¹¹ each of R¹⁰ and R¹¹ represents hydrogen. R³may represent —CH₂CHOHCH₂NH₂. In one embodiment when R³ representsC₁₋₆alkyl substituted with hydroxyl and —NR¹⁰R¹¹ one of R¹⁰ and R¹¹represents hydrogen and the other represents C₁₋₆alkyl, for example—CH₃, —CH(CH₃)₂. R³ may represent —CH₂CHOHCH₂NHCH₃ or—CH₂CHOHCH₂NHCH(CH₃)₂.

In one embodiment when R³ represents C₁₋₆alkyl substituted with hydroxyland —NR¹⁰R¹¹, one of R¹⁰ and R¹¹ represents hydrogen and the otherrepresents haloC₁₋₆alkyl, for example —CH₂CF₃. R³ may represent—CH₂CHOHCH₂NHCH₂CF₃.

In one embodiment when R³ represents C₁₋₆alkyl substituted with hydroxyland —NR¹⁰R¹¹ one of R¹⁰ and R¹¹ represents C₁₋₆alkyl, for example—CH(CH₃)₂, and the other represents —C(═O)-haloC₁₋₆alkyl, for example—C(═O)—CH₂Cl. R³ may represent —CH₂CHOHCH₂N(CH(CH₃)₂)—C(═O)CH₂Cl.

In one embodiment R³ represents hydroxyC₁₋₆alkyl, whereinhydroxyC₁₋₆alkyl includes —CD₂CD₂OH, —CH₂CH₂CH₂OH, —CD₂CD₂CD₂OH,—CH₂CHOHCH₃, —CH₂CHOHCH₂CH₃, —CH₂CHOHCH(CH₃)₂, —CH₂CH₂C(OH)(CH₃)₂,—CH₂CHOHCH₂OH or —CH₂C(CH₃)₂OH. In one embodiment R³ representsC₁₋₆alkyl substituted with one or two halo atoms and —NR¹⁰R¹¹. In oneembodiment each of R¹⁰ and R¹¹ represents hydrogen. R³ may represent—CH₂CHFCH₂NH₂.

In one embodiment R³ represents C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl. R³ may represent —CH₂C(═O)—O—CH₂CH₃ or—CH₂CH₂—C(═O)—O—CH₂CH₃R³ may represent —CH(CH₃)C(═O)—O—CH₂CH₃.

In one embodiment R³ represents C₁₋₆alkyl (for example methyl)substituted with C₁₋₆alkoxyC₁₋₆alkyl-C(═O)—. R³ mayrepresents-CH₂—C(═O)—CH₂OCH₃.

In one embodiment R³ represents C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹.

In one embodiment when R³ represents C₁₋₆alkyl substituted with—C(═O)—NR¹⁴R¹⁵, the C₁₋₆alkyl group is a straight chain alkyl group e.g.n-ethyl, n-propyl, n-butyl. In one embodiment R³ represents C₁₋₄alkylsubstituted with —C(═O)—NR¹⁴R¹⁵. In one embodiment when R³ representsC₁₋₄alkyl substituted with —C(═O)—NR¹⁴R¹⁵, the C₁₋₄alkyl group is astraight chain alkyl group e.g. n-ethyl, n-propyl, n-butyl. In oneembodiment when R³ represents C₁₋₆alkyl substituted with —C(═O)—NR¹⁴R¹⁵,the C₁₋₆alkyl group is an ethyl group (—CH₂CH₂—).

In one embodiment when R³ represents C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, R¹⁰ and R¹¹ have the following meanings:

a) R¹⁰ and R¹¹ each represent hydrogen. R³ may represent —CH₂C(═O)NH₂;b) one of R¹⁰ and R¹¹ represents hydrogen and the other representsC₁₋₆alkyl, e.g. —CH₃. R³ may represent —CH₂C(═O)NHCH₃; C₁₋₆alkyl may be—CH(CH₃)₂. R³ may represent —CH₂C(═O)NHCH(CH₃)₂ or—CH₂CH₂C(═O)NHCH(CH₃)₂;c) one of R¹⁰ and R¹¹ represents hydrogen and the other representsC₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, for example —CH₂CH₂OCH₃. R³ mayrepresent —CH₂C(═O)—NHCH₂CH₂OCH₃;d) one of R¹⁰ and R¹¹ represents hydrogen and the other representsC₁₋₆alkyl substituted with R⁶. R⁶ may be a saturated 5-memberedmonocyclic heterocycle containing one nitrogen heteroatom, for examplepyrrolidinyl. Alternatively R⁶ may be an aromatic 5-membered monocyclicheterocycle containing two nitrogen heteroatoms, for example imidazolyl.R³ may represent —CH₂C(═O)—NH—CH₂CH₂— (pyrrolidin-1-yl) or—CH₂C(═O)—NH—CH₂CH₂— (imidazol-2-yl);e) one of R¹⁰ and R¹¹ represents hydrogen and the other representshydroxyC₁₋₆alkyl, for example —CH₂CH₂OH. R³ may represent—CH₂C(═O)—NHCH₂CH₂OH; orf) one of R¹⁰ and R¹¹ represents hydrogen and the other representsC₁₋₆alkyl substituted with —NR¹⁴R¹⁵ where R¹⁴ and R¹⁵ are both hydrogen.R³ may represents —CH₂C(═O)—NHCH₂CH₂NH₂.

In one embodiment when R³ represents C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, R¹⁰ and R¹¹ have the following meanings:

a) one of R¹⁰ and R¹¹ represents hydrogen and the other representshaloC₁₋₆alkyl, for example —CH₂CF₃. R³ may represent—CH₂CH₂C(═O)—NHCH₂CF₃;b) one of R¹⁰ and R¹¹ represents C₁₋₆alkyl, for example —CH₃ and theother represents C₁₋₆alkoxy, for example —OCH₃. R³ may represent—CH₂CH₂C(═O)N(CH₃)—OCH₃.c) one of R¹⁰ and R¹¹ represents hydrogen and the other represents R⁶.R⁶ may be a six membered monocyclic heterocyclyl containing one or twonitrogen atoms and optionally substituted with one C₁₋₆alkyl orC₁₋₆alkoxy. R³ may represent —CH₂C(═O)NH-(pyridin-2-yl) wherein thepyridin-2-Y1 is substituted in the 3-position by —OCH₃, —CH₂C(═O)NH—(pyridin-6-yl) wherein the pyridin-6-Y1 is substituted in the 4-positionby —CH₃ or —CH₂C(═O)NH-(pyrimidin-2-yl) wherein the pyrimidin-2-yl) issubstituted in the 4-position by —OCH₃. R³ may represent—CH₂C(═O)NH-(pyridin-3-yl), —CH₂C(═O)NH-(pyridin-6-yl) or—CH₂C(═O)NH-(pyridin-4-yl).

In one embodiment R³ represents C₁₋₆alkyl substituted with carboxyl. R³may represent —CH₂C(═O)OH or —CH₂CH₂C(═O)OH.

In one embodiment R³ represents C₁₋₆alkyl substituted with—O—C(═O)—NR¹⁰R¹¹. In one embodiment one of R¹⁰ and R¹¹ representshydrogen and the other represents C₁₋₆alkyl, for example —CH₃. R³ mayrepresent —CH₂CH₂—O—C(═O)—NHCH₃.

In one embodiment R³ represents C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—C₁₋₆alkyl. In one embodiment R¹² represents hydrogen. R³may represent —CH₂CH₂NH—S(═O)₂—CH₃, —CH₂CH₂CH₂NH—S(═O)₂—CH₃,—CH₂CH₂NH—S(═O)₂—CH(CH₃)₂ or —CH₂CH₂NH—S(═O)₂—CH₂CH₃.

In one embodiment R³ represents C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵. In one embodiment R¹² represents hydrogen and R¹⁴and R¹⁵ each represent —CH₃. R³ may represent —CH₂CH₂NH—S(═O)₂—N(CH₃)₂or —CH₂CH₂CH₂NH—S(═O)₂—N(CH₃)₂.

In one embodiment R³ represents C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, R⁹ represents 5-memberedunsaturated ring fused to a 6-membered unsaturated ring, for example afuran ring fused to a pyridine ring, or a pyrrole ring fused to apyridine ring, wherein the pyrrole ring is optionally substituted withone C₁₋₄alkyl, for example —CH₃. In one embodiment R⁹ represents1H-pyrrolo[3,2-b]pyridinyl, 1-methyl-1H-pyrrolo[3,2-b]pyridinyl orfuro[3,2-b]pyridinyl.

In one embodiment R³ represents C₁₋₆alkyl substituted with hydroxyl andR⁹.

In one embodiment when R³ represents C₁₋₆alkyl substituted with hydroxyland R⁹, R⁹ represents a saturated 5 membered monocyclic heterocyclylcontaining one nitrogen heteroatom, for example pyrrolidinyl. R³ mayrepresent propyl substituted with —OH and 1-pyrrolidinyl.

In one embodiment when R³ represents C₁₋₆alkyl substituted with hydroxyland R⁹, R⁹ represents a saturated 5 membered monocyclic heterocyclylcontaining one nitrogen heteroatom, for example pyrrolidinyl, and theheterocyclyl is substituted. For example the heterocyclyl is substitutedwith

a) two halo's, for example two fluorines. R³ may represent propylsubstituted with —OH and 1-pyrrolidinyl where the 1-pyrrolidinyl issubstituted at the 3 position by two fluorines; orb) a cyano group. R³ may represent propyl substituted with —OH and1-pyrrolidinyl where the 1-pyrrolidinyl is substituted at the 3 positionby a cyano group.

In one embodiment when R³ represents C₁₋₆alkyl substituted with hydroxyland R⁹, R⁹ represents a saturated 6 membered monocyclic heterocyclecontaining one nitrogen and one oxygen heteroatom, for examplemorpholinyl. R³ may represent propyl substituted with —OH and4-morpholinyl.

In one embodiment when R³ represents C₁₋₆alkyl substituted with hydroxyland R⁹, R⁹ represents a saturated 6 membered monocyclic heterocyclecontaining one nitrogen heteroatom, for example piperidinyl. R³ mayrepresent propyl substituted with —OH and 1-piperidinyl.

In one embodiment when R³ represents C₁₋₆alkyl substituted with hydroxyland R⁹, R⁹ represents an aromatic 5 membered monocyclic heterocyclecontaining three nitrogen heteroatoms, for example 1,2,4-triazolyl. Theheterocycle may be substituted by one C₁₋₄alkyl, for example —CH₃. R³may represent propyl substituted with —OH and 2-(1,2,4-triazolyl)substituted in the 3 position by —CH₃.

In one embodiment when R³ represents C₁₋₆alkyl substituted with hydroxyland R⁹, R⁹ represents an aromatic 5 membered monocyclic heterocyclecontaining two nitrogen heteroatoms, for example imidazolyl. Theheterocycle may be substituted by one C₁₋₄alkyl, for example —CH₃. R³may represent propyl substituted with —OH and 1-imidazolyl substitutedin the 2 position by —CH₃.

In one embodiment when R³ represents C₁₋₆alkyl substituted with hydroxyland R⁹, R⁹ represents an optionally substituted bicyclic heterocyclylcontaining one nitrogen heteroatom, said bicyclic heterocyclyl may besubstituted for example with two ═O groups. R³ may represent propylsubstituted with hydroxyl and isoindole-1,3-dione.

In one embodiment R³ represents —C₁₋₆alkyl-C(R¹²)═N—O—R¹². R¹² mayindependently be chosen from hydrogen and C₁₋₄alkyl optionallysubstituted with C₁₋₄alkyloxy, for example —CH₃ or —CH(CH₃)₂. R³ mayrepresent —CH₂C(CH₃)═N—O—H, —CH₂C(CH₂OCH₃)═N—O—H or—CH₂C(CH(CH₃)₂)═N—O—H.

In one embodiment R³ represents —S(═O)₂—NR¹⁴R¹⁵, where R¹⁴ and R¹⁵ mayeach be C₁₋₄alkyl. R³ may be —S(═O)₂—N(CH₃)₂.

In one embodiment R³ represents C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl. R³ may be —CH₂CH₂—S(═O)₂—CH₃.

In one embodiment R³ represents C₁₋₆alkyl substituted with —C(═O)—R⁹. R⁹may represent a saturated 5-membered monocyclic heterocycle containingone nitrogen heteroatom, for example pyrrolidinyl. R³ may represent—CH₂—C(═O)—R⁹ and R⁹ is 1-pyrrolidinyl.

In one embodiment R³ represents C₂₋₆alkenyl substituted with R⁹. R⁹ mayrepresent an optionally substituted aromatic 6-membered monocyclicheterocycle containing one or two nitrogen heteroatoms, for examplepyridinyl or pyrimidinyl. The heterocyclyl may be substituted, forexample with one C₁₋₄alkyl or one C₁₋₄alkoxy substituent, for example—CH₃ or —OCH₃. R³ may represent —CH₂CH═CH-(2-pyrimidinyl),—CH₂CH═CH-(2-pyrimidinyl) wherein the 2-pyrimidinyl is substituted inthe 4-position by —OCH₃, —CH₂CH═CH-(2-pyridinyl) wherein the 2-pyridinylis substituted in the 4-position by —CH₃ or —CH₂CH═CH-(2-pyridinyl)wherein the 2-pyridinyl is substituted in the 3-position by —OCH₃.

In one embodiment R³ represents C₂₋₆alkynyl substituted with R⁹. R⁹ mayrepresent an optionally substituted aromatic 5-membered monocyclicheterocycle containing two nitrogen heteroatoms, for example imidazolyl.The heterocyclyl may be substituted, for example substituted with oneC₁₋₄alkyl substituent, for example —CH₃. R³ may represent—CH₂—C≡C-(2-imidazoly) wherein the 2-imidazolyl is substituted in the 1position by —CH₃ or —CH₂—C≡C-(5-imidazolyl) wherein the 5-imidazolyl issubstituted in the 1 position by —CH₃.

In one embodiment R³ represents C₂₋₆alkynyl substituted with R⁹.

In one embodiment when R³ represents C₂₋₆alkynyl substituted with R⁹, R⁹represents an optionally substituted aromatic 6-membered monocyclicheterocycle containing one or two nitrogen heteroatoms, for examplepyridinyl, pyrimidinyl or pyrazinyl. R³ may represent —CH₂—C≡C—(4-pyridinyl), —CH₂—C≡C— (3-pyridinyl), —CH₂—C≡C— (2-pyridinyl),—CH₂—C≡C— (2-pyrimidinyl), —CH₂—C≡C— (6-pyrazinyl).

In one embodiment when R³ represents C₂₋₆alkynyl substituted with R⁹, R⁹represents an optionally substituted aromatic 6-membered monocyclicheterocycle containing one or two nitrogen heteroatoms, for examplepyridinyl, pyrimidinyl or pyrazinyl and the heterocyclyl may besubstituted, for example substituted with:

a) one hydroxyC₁₋₄alkyl. R³ may represent —CH₂—C≡C— (6-pyridinyl)substituted in the 2 or 4-position with —CH₂OH;b) one C₁₋₄alkoxy, for example —OCH₃, —OCH₂CH₃. R³ may represent—CH₂—C≡C— (4-pyridinyl) substituted in the 6-position with —OCH₃,—CH₂—C≡C— (2-pyridinyl) substituted in the 3 or 5-position with —OCH₃,—CH₂—C≡C— (2-pyrimidinyl) substituted in the 4 or 6-position with —OCH₃,—CH₂—C≡C— (6-pyridinyl) substituted in the 2, 4 or 5-position with—OCH₃, —CH₂—C≡C— (6-pyrimidinyl) substituted in the 4-position with—OCH₃, —CH₂—C≡C— (5-pyrazinyl) substituted in the 6-position with —OCH₃,—CH₂—C≡C— (2-pyrimidinyl) substituted in the 6-position with —OCH₂CH₃,—C(CH₃)₂—C≡C— (2-pyrimidinyl) substituted in the 4-position with—OCH₃—CH₂—C≡C— (2-pyrimidinyl) substituted in the 4-position with—OCH(CH₃)₂;c) one cyano. R³ may represent —CH₂—C≡C— (6-pyridinyl) substituted inthe 2 or the 4-position with cyano, —CH₂—C≡C— (4-pyridinyl) substitutedin the 5 or 6-position with cyano;d) one —NR¹⁴R¹⁵. R³ may represent —CH₂—C≡C— (6-pyridinyl) substituted inthe 2 or 4-position with —NH₂, —CH₂—C≡C— (6-pyrimidinyl) substituted inthe 2-position with —NH₂, —CH₂—C≡C— (2-pyridinyl) substituted in the3-position with —NH₂, —CH₂—C≡C— (3-pyrazinyl) substituted in the6-position with —NH₂, —CH₂—C≡C— (6-pyridinyl) substituted in the5-position with —NHCH₃,e) one C₁₋₄alkyl, for example —CH₃ or —CH₂CH₃. R³ may represent—CH₂—C≡C— (6-pyridinyl) substituted in the 3 or 4-position with —CH₃,—CH₂—C≡C— (2-pyridinyl) substituted in the 3-position with —CH₃,—CH₂—C≡C— (2-pyrimidinyl) substituted in the 4-position with —CH₃,—CH₂—C≡C— (2-pyrimidinyl) substituted in the 6-position with —CH₂CH₃,f) one C₁₋₄alkyl, for example —CH₃ and one —NR¹⁴R¹⁵, for example —NH₂.R³ may represent —CH₂—C≡C— (6-pyrimidinyl) substituted in the 2-positionwith —CH₃ and in the 4-position with —NH₂;g) one halogen, for example —Cl and one —NR¹⁴R¹⁵, for example —NH₂. R³may represent —CH₂—C≡C— (6-pyrimidinyl) substituted in the 2-positionwith —NH₂ and in the 4-position with —Cl,h) one halogen, for example —Br, —Cl or —F. R³ may represent —CH₂—C≡C—(2-pyrazinyl) substituted in the 3-position with —Cl, —CH₂—C≡C—(3-pyrazinyl) substituted in the 5-position with —Cl, —CH₂—C≡C—(2-pyridinyl) substituted in the 3-position with —F, —CH₂—C≡C—(5-pyridinyl) substituted in the 6-position with —Br;i) one —C(═O)—NR¹⁴R¹⁵. R³ may represent —CH₂—C≡C— (6-pyridinyl)substituted in the 4-position with —C(═O)—NH₂;j) one C₁₋₄alkyl-O—C(═O)—. R³ may represent —CH₂—C≡C— (6-pyridinyl)substituted in the 5-position with CH₃—O—C(═O)—, —CH₂—C≡C—(2-pyrimidinyl) substituted in the 6-position with CH₃—O—C(═O)—;k) one haloC₁₋₄alkyl. R³ may represent —CH₂—C≡C— (2-pyridinyl)substituted in the 3-position with —CF₃.

In one embodiment when R³ represents C₂₋₆alkynyl substituted with R⁹, R⁹represents an optionally substituted aromatic 5-membered monocyclicheterocyclyl containing one nitrogen and one sulphur heteroatom, forexample thiazolyl. R³ may represent —CH₂—C≡C— (5-thiazolyl).

In one embodiment when R³ represents C₂₋₆alkynyl substituted with R⁹, R⁹represents an optionally substituted phenyl. R³ may be —CH₂—C≡C—(phenyl). The phenyl may be substituted, for example with oneC₁₋₄alkoxy. R³ may represent —CH₂—C≡C— (phenyl) where the phenyl issubstituted in the 5-position by —OCH₃.

In one embodiment when R³ represents C₂₋₆alkynyl substituted with R⁹, R⁹represents an optionally substituted saturated 4-membered monocyclicheterocycle containing one nitrogen heteroatom, for example azetidinyl.The heterocyclyl may be substituted, for example with:

a) one hydroxyl and one C₁₋₄alkyl-O—C(═O)—. R³ may represent —CH₂—C≡C—(3-azetidinyl) substituted in the 1-position by (CH₃)₃C—O—C(═O)— and inthe 3-position by —OH;b) one hydroxyl. R³ may represent —CH₂—C≡C— (3-azetidinyl) substitutedin the 3-position by —OH.

In one embodiment when R³ represents C₂₋₆alkynyl substituted with R⁹, R⁹represents an optionally substituted saturated 5-membered monocyclicheterocycle containing one nitrogen heteroatom, for examplepyrrolidinyl. The heterocyclyl may be substituted, for example with:

a) one hydroxyl and one C₁₋₄alkyl-O—C(═O)—. R³ may represent —CH₂—C≡C—(3-pyrrolidinyl) substituted in the 1-position by (CH₃)₃C—O—C(═O)— andin the 3-position by —OH;b) one hydroxyl. R³ may represent —CH₂—C≡C— (3-pyrrolidinyl) substitutedin the 3-position by —OH.

In one embodiment when R³ represents C₂₋₆alkynyl substituted with R⁹, R⁹represents an optionally substituted saturated 6-membered monocyclicheterocycle containing one nitrogen heteroatom, for example piperidinyl.R³ may represent —CH₂—C≡C— (4-piperidinyl). The heterocyclyl may besubstituted, for example with:

a) one hydroxyl. R³ may represent —CH₂—C≡C— (4-piperidinyl) substitutedin the 4-position by —OH;b) one C₁₋₄alkyl-O—C(═O)—. R³ may represent —CH₂—C≡C— (4-piperidinyl)substituted in the 1-position by (CH₃)₃C—O—C(═O)—.

In one embodiment when R³ represents C₂₋₆alkynyl substituted with R⁹, R⁹represents an optionally substituted saturated 5-membered monocyclicheterocycle containing one oxygen heteroatom, for exampletetrahydrofuranyl. The heterocyclyl may be substituted, for example withone hydroxyl. R³ may represent —CH₂—C≡C— (4-tetrahydrofuranyl)substituted in the 3-position by —OH.

In one embodiment when R³ represents C₂₋₆alkynyl substituted with R⁹, R⁹represents an optionally substituted saturated 6-membered monocyclicheterocycle containing one oxygen heteroatom, for exampletetrahydropyranyl. The heterocyclyl may be substituted, for example withone hydroxyl. R³ may represent —CH₂—C≡C— (4-tetrahydropyranyl)substituted in the 4-position by —OH.

In one embodiment when R³ represents C₂₋₆alkynyl substituted with R⁹, R⁹represents a C₃₋₈cycloalkyl, for example cyclohexyl.

R³ may represent —CH₂—C≡C— (cyclohexyl).

In one embodiment R³ represents C₂₋₆alkynyl (e.g. —CH₂—C≡C—) substitutedwith R⁹, wherein R⁹ represents C₃₋₈cycloalkyl or 3 to 12 memberedmonocyclic or bicyclic heterocyclyl containing at least one heteroatomselected from N, O or S, said C₃₋₈cycloalkyl or 3 to 12 memberedmonocyclic or bicyclic heterocyclyl each optionally and eachindependently being substituted with 1, 2, 3, 4 or 5 substituents asdefined herein.

In one embodiment R³ represents C₂₋₆alkynyl (e.g. —CH₂—C≡C—) substitutedwith R⁹, wherein R⁹ represents an optionally substituted 4 to 8-memberedmonocyclic or bridged heterocyclyl, for example R⁹ represents anoptionally substituted azetidinyl, pyrrolidinyl, imidazolyl, thiazolyl,pyridinyl, pyrimidinyl, pyrazinyl, piperidinyl, tetrahydrofuranyl,tetrahydropyranyl, or 2,5-diaza-bicyclo[2.2.1]heptanyl.

In one embodiment R³ represents C₂₋₆alkynyl (e.g. —CH₂—C≡C—) substitutedwith R⁹, wherein R⁹ represents

-   -   an optionally substituted aromatic 5- or 6-membered monocyclic        heterocyclyl, for example imidazolyl, thiazolyl, pyridinyl,        pyrimidinyl or pyrazinyl.    -   an optionally substituted saturated 4-, 5-, or 6-membered        monocyclic heterocyclyl, for example azetidinyl, pyrrolidinyl,        piperidinyl, tetrahydrofuranyl, tetrahydropyranyl.    -   an optionally substituted 6 to 8 membered bridged heterocyclyl        group, for example 2,5-diaza-bicyclo[2.2.1]heptanyl.    -   a C₃₋₈cycloalkyl, for example cyclohexyl.

In one embodiment R³ represents C₂₋₆alkynyl (e.g. —CH₂—C≡C—) substitutedwith R⁹, wherein R⁹ represents

-   -   an optionally substituted aromatic 5-membered monocyclic        heterocycle containing two nitrogen heteroatoms, for example        imidazolyl,    -   an optionally substituted aromatic 6 membered monocyclic        heterocycle containing one nitrogen heteroatom, for example        pyridinyl,    -   an optionally substituted aromatic 6 membered monocyclic        heterocycle containing one or two nitrogen heteroatoms, for        example pyridinyl, pyrimidinyl or pyrazinyl    -   an optionally substituted aromatic 5-membered monocyclic        heterocyclyl containing one nitrogen and one sulphur heteroatom,        for example thiazolyl,    -   an optionally substituted saturated 4-membered monocyclic        heterocycle containing one nitrogen heteroatom, for example        azetidinyl,    -   an optionally substituted saturated 5-membered monocyclic        heterocycle containing one nitrogen heteroatom, for example        pyrrolidinyl,    -   an optionally substituted saturated 5-membered monocyclic        heterocycle containing one oxygen heteroatom, for example        tetrahydrofuranyl,    -   an optionally substituted saturated 6-membered monocyclic        heterocycle containing one oxygen heteroatom, for example        tetrahydropyranyl,    -   a C₃₋₈cycloalkyl, for example cyclohexyl or    -   a 6 to 8 membered bridged heterocyclyl group, for example        2,5-diaza-bicyclo[2.2.1]heptanyl.

In one embodiment when R³ represents C₁₋₆alkyl substituted with R⁹, R⁹represents an optionally substituted 6 to 8 membered bridgedheterocyclyl group, for example 2,5-diaza-bicyclo[2.2.1]heptanyloptionally substituted by —C(═O)—O—C₄alkyl.

In one embodiment R³ represents C₁₋₆alkyloxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groups.R³ may represent —CH₂CHOHCH₂OCH₃.

In one embodiment R³ represents C₂₋₆alkenyl. R³ may represent—CH₂—CH═CH₂.

In one embodiment R³ represents C₂₋₆alkynyl. R³ may represent—CH₂—C≡C—H. R³ may represent —C(CH₃)₂—C≡C—H.

In one embodiment R³ represents R¹³.

In one embodiment when R³ represents R¹³, R¹³ represents a saturated4-membered monocyclic heterocycle containing one oxygen heteroatom. R³may represent 3-oxetanyl.

In another embodiment when R³ represents R¹³, R¹³ represents anoptionally substituted C₃₋₈cycloalkyl. For example the C₃₋₈cycloalkylmay be substituted with one NR¹⁴R¹⁵ where one of R¹⁴ and R¹⁵ representshydrogen and the other represents C₁₋₄alkyl optionally substituted withhydroxyl, for example —CH(CH₃)₂. R³ may represent cyclohexanylsubstituted in the 4 position by —NH—CH(CH₃)₂.

In one embodiment of the invention R³ represents C₁₋₆alkyl substitutedby R⁹, wherein R⁹ is a saturated heterocyclyl substituted by R¹³,wherein R¹³ is a saturated heterocyclyl which is optionally substituted,for example substituted by —C(═O)—C₁₋₆alkyl. In one embodiment R⁹ ispiperazinyl substituted by R¹³, wherein R¹³ is piperidinyl substitutedby —C(═O)—C₁₋₆alkyl.

In one embodiment of the invention R³ represents C₁₋₆alkyl substitutedwith —P(═O)(OC₁₋₆alkyl)₂. R³ may represent —CH₂CH₂P(═O)(OCH₂CH₃)₂.

In one embodiment of the invention R¹ represents C₁₋₆alkyl, for example—CH₃, each R^(1a) represents hydrogen, n represents an integer equal to2 and each R² represents C₁₋₄alkoxy, for example CH₃O—, and R³represents C₁₋₆alkyl substituted with —NR¹⁰R¹¹, for example—CH₂CH₂NHCH(CH₃)₂.

In a further embodiment of the invention R¹ represents C₁₋₆alkyl, forexample —CH₃, each R^(1a) represents hydrogen, n represents an integerequal to 2 and each R² represents C₁₋₄alkoxy, for example CH₃O—, R³represents C₁₋₆alkyl substituted with —NR¹⁰R¹¹, for example—CH₂CH₂—CH₂—NHCH₂CF₃.

In a further embodiment of the invention R¹ represents C₁₋₆alkyl, forexample —CH₃, each R^(1a) represents hydrogen, n represents an integerequal to 2 and each R² represents C₁₋₄alkoxy, for example CH₃O—, R³represents C₁₋₆alkyl substituted with —NR¹⁰R¹¹, for example —CH₂CH₂NH₂.

In one embodiment of the invention R¹ represents C₁₋₆alkyl, for example—CH₃, each R^(1a) represents hydrogen, n represents an integer equal to2 and each R² represents C₁₋₄alkoxy, for example CH₃O—, and R³represents C₂₋₆alkynyl substituted with —R⁹, for example —CH₂—C≡C—(2-pyridinyl).

In one embodiment of the invention R¹ represents C₁₋₆alkyl, for example—CH₃, each R^(1a) represents hydrogen, n represents an integer equal to2 and each R² represents C₁₋₄alkoxy, for example CH₃O—, and R³represents C₂₋₆alkynyl substituted with —R⁹, for example —CH₂—C≡C—(2-pyridinyl) substituted in the 3-position by —OCH₃.

In one embodiment of the invention R¹ represents C₁₋₆alkyl, for example—CH₃, each R^(1a) represents hydrogen, n represents an integer equal to2 and each R² represents C₁₋₄alkoxy, for example CD₃O—, and R³represents C₁₋₆alkyl substituted with —NR¹⁰R¹¹, for example R³ mayrepresent —CD₂-CD₂-NHCH(CH₃)₂.

In one embodiment of the invention R¹ represents C₁₋₆alkyl, for example—CH₃, each R^(1a) represents hydrogen, n represents an integer equal to2 and each R² represents C₁₋₄alkoxy, for example CH₃O—, and R³represents C₂₋₆alkynyl substituted with —R⁹, for example —CH₂—C≡C—(6-pyridinyl) substituted in the 2-position by —NH₂.

In one embodiment of the invention R¹ represents C₁₋₆alkyl, for example—CH₃, each R^(1a) represents hydrogen, n represents an integer equal to2 and each R² represents C₁₋₄alkoxy, for example CH₃O—, and R³represents C₂₋₆alkynyl substituted with —R⁹, for example —CH₂—C≡C—(2-pyrimidinyl) substituted in the 4-position by —OCH₃.

In one embodiment of the invention R¹ represents C₁₋₆alkyl, for example—CH(CH₃)₂, each R^(1a) represents hydrogen, n represents an integerequal to 2 and each R² represents C₁₋₄alkoxy, for example CD₃O—, and R³represents C₂₋₆alkynyl substituted with —R⁹, for example —CH₂—C≡C—(4-pyridinyl).

In one embodiment of the invention R¹ represents C₁₋₆alkyl, for example—CH(CH₃)₂,

each R^(1a) represents hydrogen, n represents an integer equal to 2 andeach R² represents C₁₋₄alkoxy, for example CH₃O—, and R³ representsC₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups or with —O—C(═O)—C₁₋₆alkyl, for example—CH₂CHOHCH₂OCH₃.

In one embodiment of the invention R¹ represents C₁₋₆alkyl, for example—CH₃, each R^(1a) represents hydrogen, n represents an integer equal to2 and each R² represents C₁₋₄alkoxy, for example CH₃O—, and R³represents C₂₋₆alkynyl substituted with —R⁹, for example —CH₂—C≡C—(6-pyridinyl) substituted in the 4-position by —CH₃.

In one embodiment of the invention R¹ represents C₁₋₆alkyl substitutedwith —NR⁴R⁵, for example —CH₂CH₂CH₂NH₂, each R^(1a) represents hydrogen,n represents an integer equal to 2 and each R² represents C₁₋₄alkoxy,for example CH₃O—, and R³ represents hydroxyhaloC₁₋₆alkyl, for example—CH₂CHOHCF₃.

In one embodiment of the invention R¹ represents C₁₋₆alkyl, for example—CH₃, each R^(1a) represents hydrogen, n represents an integer equal to4 and two R² represent C₁₋₄alkoxy, for example CH₃O—, and two R²represent halogen, for example F, and R³ represents C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, for example —CH₂CH₂NH(CH(CH₃)₂).

In one embodiment of the invention R¹ represents C₁₋₆alkyl, for example—CH₃, each R^(1a) represents hydrogen, n represents an integer equal to2 and each R² represents C₁₋₄alkoxy, for example CH₃O—, and R³represents C₁₋₆alkyl substituted with —NR¹⁰R¹¹, for example—CH₂CH₂CH₂NH₂.

In a further embodiment the compound of formula (I) as defined herein isselected from the following compounds or is one of the followingcompounds:

-   N-(3,5-Dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine    (compound 84)-   3-{4-[3-(4-{7-[(Cyclopropylmethyl)(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1H-pyrazol-1-yl)propyl]piperazin-1-yl}propan-1-ol    or HCl salt thereof (compound 130)-   N-(3,5-Dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine    (compound 4)-   2-[4-(7-{(Cyclopropylmethyl)[3-(2-hydroxyethoxy)-5-methoxyphenyl]amino}quinoxalin-2-yl)-1H-pyrazol-1-yl]ethanol    or HCl salt thereof (compound 131)-   N-(3,5-Dimethoxyphenyl)-N-[3-(1-methyl-1H-imidazol-2-yl)prop-2-yn-1-yl]-3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-amine    (compound 300)-   1-(3-{(3,5-Dimethoxyphenyl)[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}propyl)pyrrolidin-2-one    (compound 132)-   (3S)-1-(2-{(3,5-Dimethoxyphenyl)[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}ethyl)pyrrolidine-3-carbonitrile    (compound 133)-   N-(3,5-Dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-N′-(2,2,2-trifluoroethyl)propane-1,3-diamine    (compound 5)-   2-(4-{7-[(3,5-Dimethoxyphenyl){2-[(1-methylethyl)amino]ethyl}amino]quinoxalin-2-yl}-1H-pyrazol-1-yl)-N-methylacetamide    or HCl salt thereof (compound 134)-   N-(3,5-Dimethoxyphenyl)-N-[3-(1-ethyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-N′-(1-methylethyl)ethane-1,2-diamine    or HCl salt thereof (compound 135)-   N-(3,5-Dimethoxyphenyl)-N′-(1-methylethyl)-N-{3-[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazol-4-yl]quinoxalin-6-yl}ethane-1,2-diamine    or HCl salt thereof (compound 136)-   (2S)-3-{(3,5-Dimethoxyphenyl)[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}propane-1,2-diol    (compound 98)-   N-(3,5-Dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine    or HCl salt thereof (compound 137)-   N-(3,5-Dimethoxyphenyl)-N-(1H-imidazol-2-ylmethyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-amine    (compound 99)-   3-{(Cyclopropylmethyl)[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-5-fluoro-N-methylbenzamide    (compound 138)-   1-{(3,5-Dimethoxyphenyl)[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-3-[(2,2,2-trifluoroethyl)amino]propan-2-ol    (compound 139)-   3-[(2-{(3,5-Dimethoxyphenyl)[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}ethyl)amino]propanenitrile    (compound 140)-   4-{(3,5-Dimethoxyphenyl)[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-2-methylbutan-2-ol    (compound 141)-   (2S)-1-{(3,5-Dimethoxyphenyl)[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-3-[(2,2,2-trifluoroethyl)amino]propan-2-ol    (compound 142)-   N-[2-(4-Acetylpiperazin-1-yl)ethyl]-N-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-amine    (compound 143)-   4-(2-{(3,5-Dimethoxyphenyl)[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}ethyl)piperazin-2-one    (compound 144)-   (2S)-1-{(3,5-Dimethoxyphenyl)[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-3-[(1-methylethyl)amino]propan-2-ol    or HCl salt thereof (compound 145)-   N-(3,5-Dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N-(pyrazin-2-ylmethyl)quinoxalin-6-amine    (compound 146)-   N-(3,5-Dimethoxyphenyl)-N-{3-[1-(1-methylethyl)-1H-pyrazol-4-yl]quinoxalin-6-yl}-N′-(2,2,2-trifluoroethyl)propane-1,3-diamine    or HCl salt thereof (compound 147)-   (2R*)-3-{(3,5-Dimethoxyphenyl)[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-1,1,1-trifluoropropan-2-ol    (relative stereochemistry) (Compound 148)-   (2S*)-3-{(3,5-Dimethoxyphenyl)[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-1,1,1-trifluoropropan-2-ol    (relative stereochemistry) (compound 149);-   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof.

In a further embodiment the compound of formula (I) as defined herein isselected from the following compounds or is one of the followingcompounds:

-   N-(3,5-Dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-N′-(2,2,2-trifluoroethyl)propane-1,3-diamine    (compound 5)-   N-(3,5-Dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine    (compound 4)-   N-(3,5-Dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine    (compound 84)-   N-(3,5-Dimethoxyphenyl)-N-{3-[1-(1-methylethyl)-1H-pyrazol-4-yl]quinoxalin-6-yl}-N′-(2,2,2-trifluoroethyl)propane-1,3-diamine    or HCl salt thereof (compound 147)-   N-(3,5-Dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine    or HCl salt thereof (compound 137)-   N-(3,5-Dimethoxyphenyl)-N′-(1-methylethyl)-N-{3-[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazol-4-yl]quinoxalin-6-yl}ethane-1,2-diamine    or HCl salt thereof (compound 136)-   N-(3,5-Dimethoxyphenyl)-N-[3-(1-ethyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-N′-(1-methylethyl)ethane-1,2-diamine    or HCl salt thereof (compound 135)-   2-(4-{7-[(3,5-Dimethoxyphenyl){2-[(1-methylethyl)amino]ethyl}amino]quinoxalin-2-yl}-1H-pyrazol-1-yl)-N-methylacetamide    or HCl salt thereof (compound 134)-   N-(3,5-Dimethoxyphenyl)-N-[3-(1-methyl-1H-imidazol-2-yl)prop-2-yn-1-yl]-3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-amine    (compound 300);-   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof.

In a further embodiment the compound of formula (I) as defined herein isselected from the following compounds or is one of the followingcompounds:

-   N-(3,5-Dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-N′-(2,2,2-trifluoroethyl)propane-1,3-diamine    (compound 5)-   N-(3,5-Dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine    (compound 4)-   N-(3,5-Dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine    (compound 84);    a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof.

In a further embodiment the compound of formula (I) as defined herein isselected from the following compounds or is one of the followingcompounds:

-   N-(3,5-Dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]propane-1,3-diamine;    (compound 93)-   2-(4-{7-[(3,5-Dimethoxyphenyl){2-[(1-methylethyl)amino]ethyl}amino]quinoxalin-2-yl}-1H-pyrazol-1-yl)ethanol;    (compound 691)-   N-(3,5-Dimethoxyphenyl)-N′-(1-methylethyl)-N-(3-{1-[2-(methylsulfonyl)ethyl]-1H-pyrazol-4-yl}quinoxalin-6-yl)ethane-1,2-diamine;    (compound 678)-   N-(3,5-Dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N-(3-pyridin-2-ylprop-2-yn-1-yl)quinoxalin-6-amine;    (compound 691)-   N-(3,5-Dimethoxyphenyl)-N-[3-(3-methoxypyridin-2-yl)prop-2-yn-1-yl]-3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-amine;    (compound 652)-   N-{3,5-Bis[(²H₃)methyloxy]phenyl}-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl](²H₄)ethane-1,2-diamine;    (compound 618)-   N-[3-(6-Aminopyridin-2-yl)prop-2-yn-1-yl]-N-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-amine;    (compound 689)-   N-(3,5-Dimethoxyphenyl)-N-[3-(4-methoxypyrimidin-2-yl)prop-2-yn-1-yl]-3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-amine;    (compound 688)-   N-{3,5-Bis[(²H₃)methyloxy]phenyl}-3-[1-(1-methylethyl)-1H-pyrazol-4-yl]-N-(3-pyridin-4-ylprop-2-yn-1-yl)quinoxalin-6-amine;    (compound 653)-   1-[(3,5-Dimethoxyphenyl){3-[1-(1-methylethyl)-1H-pyrazol-4-yl]quinoxalin-6-yl}amino]-3-methoxypropan-2-ol;    or its hydrochloric acid salt; (compound 657)-   N-(3,5-Dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N-[3-(4-methylpyridin-2-yl)prop-2-yn-1-yl]quinoxalin-6-amine;    (compound 634)-   3-[{3-[1-(3-Aminopropyl)-1H-pyrazol-4-yl]quinoxalin-6-yl}(3,5-dimethoxyphenyl)amino]-1,1,1-trifluoropropan-2-ol;    or an enantiomer thereof; (compound 660 and 661)-   N-(2,6-Difluoro-3,5-dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine    (compound 687);    a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof.

According to an aspect of the invention there is provided compounds offormula (I):

including any tautomeric or stereochemically isomeric form thereof,wherein

-   n represents an integer equal to 0, 1, 2, 3 or 4;-   R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl, hydroxyC₁₋₆alkyl,    haloC₁₋₆alkyl, cyanoC₁₋₄alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each    C₁₋₆alkyl may optionally be substituted with one or two hydroxyl    groups, C₁₋₆alkyl substituted with —NR⁴R⁵, C₁₋₆alkyl substituted    with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl    substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —NH—S(═O)₂—C₁₋₆alkyl, R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkyl    substituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶, or    C₁₋₆alkyl substituted with —Si(CH₃)₃;-   each R^(1a) is independently selected from hydrogen, C₁₋₄alkyl,    hydroxyC₁₋₄alkyl, C₁₋₄alkyl substituted with di(C₁₋₄alkyl)amino, and    C₁₋₄alkyl substituted with one or more fluoro atoms;-   each R² is independently selected from hydroxyl, halogen, cyano,    C₁₋₄alkyl, C₂₋₄alkenyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,    hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy,    C₁₋₄alkoxyC₁₋₄alkyl, R¹³, C₁₋₄alkoxy substituted with R¹³,    —C(═O)—R¹³, C₁₋₄alkyl substituted with NR⁷R⁸, C₁₋₄alkoxy substituted    with NR⁷R⁸, —NR⁷R⁸ and —C(═O)—NR⁷R⁸; or when two R² groups are    attached to adjacent carbon atoms they may be taken together to form    a radical of formula —O—(C(R¹⁷)₂)_(p)—O— wherein R¹⁷ represents    hydrogen or fluorine and p represents 1 or 2;-   R³ represents C₁₋₆alkyl, hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,    hydroxyC₂₋₆alkynyl, haloC₁₋₆alkyl, haloC₁₋₆alkyl optionally    substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may    optionally be substituted with one or two hydroxyl groups,    C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be    substituted with one or two hydroxyl groups or with    —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹, C₁₋₆alkyl    substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted with hydroxyl and    —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogens and    —NR¹⁰R¹¹, C₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl    substituted with —O—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with    carboxyl, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl    substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —NR¹²—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with and R⁹ and    optionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl    substituted with hydroxyl and R⁹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹²,    —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl,    C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted    with —C(═O)—R⁹, C₂₋₆alkenyl substituted with R⁹, C₂₋₆alkynyl    substituted with R⁹, hydroxyC₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl,    R¹³ or C₁₋₆alkyl substituted with C₁₋₆alkoxyC₁₋₆alkyl-C(═O)— or    C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂;-   R⁴ and R⁵ each independently represent hydrogen, C₁₋₆alkyl,    hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,    C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be    substituted with one or two hydroxyl groups, —S(═O)₂—C₁₋₆alkyl,    —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with    —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,    C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted    with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with    —NH—S(═O)₂—NR¹⁴R¹⁵, R¹³ or C₁₋₆alkyl substituted with R¹³;-   R⁶ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to    7-membered monocyclic heterocyclyl containing at least one    heteroatom selected from N, O or S; said C₃₋₈cycloalkyl,    C₃₋₈cycloalkenyl, phenyl, 4 to 7-membered monocyclic heterocyclyl,    optionally and each independently being substituted by 1, 2, 3, 4 or    5 substituents, each substituent independently being selected from    cyano, C₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyl, carboxyl,    hydroxyC₁₋₆alkyl, halogen, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkyl-O—C(═O)—, —NR¹⁴R¹⁵,    —C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkyl    substituted with —C(═O)—NR¹⁴R¹⁵, —S(═O)₂—C₁₋₆alkyl,    —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with    —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,    C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted    with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted with    —NH—S(═O)₂—NR¹⁴R¹⁵;-   R⁷ and R⁸ each independently represent hydrogen, C₁₋₆alkyl,    hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl or    C₁₋₆alkoxyC₁₋₆alkyl;-   R⁹ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, naphthyl, or    3 to 12 membered monocyclic or bicyclic heterocyclyl containing at    least one heteroatom selected from N, O or S, said C₃₋₈cycloalkyl,    C₃₋₈cycloalkenyl, phenyl, naphthyl, or 3 to 12 membered monocyclic    or bicyclic heterocyclyl each optionally and each independently    being substituted with 1, 2, 3, 4 or 5 substituents, each    substituent independently being selected from ═O, C₁₋₄alkyl,    hydroxyl, carboxyl, hydroxyC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl,    C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkyl substituted with C₁₋₄alkyl-O—C(═O)—,    C₁₋₄alkyl-C(═O)—, C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl may    optionally be substituted with one or two hydroxyl groups, halogen,    haloC₁₋₄alkyl, hydroxyhaloC₁₋₄alkyl, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵,    C₁₋₄alkyl substituted with —NR¹⁴R¹⁵, C₁₋₄alkyl substituted with    —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkoxy, —S(═O)₂—C₁₋₄alkyl,    —S(═O)₂-haloC₁₋₁₄alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with    —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with —NH—S(═O)₂—C₁₋₄alkyl,    C₁₋₄alkyl substituted with —NH—S(═O)₂-haloC₁₋₁₄alkyl, C₁₋₄alkyl    substituted with —NH—S(═O)₂—NR¹⁴R¹⁵, R¹³, —C(═O)—R¹³, C₁₋₄alkyl    substituted with R¹³, phenyl optionally substituted with R¹⁶,    phenylC₁₋₆alkyl wherein the phenyl is optionally substituted with    R¹⁶, a 5 or 6-membered aromatic monocyclic heterocyclyl containing    at least one heteroatom selected from N, O or S wherein said    heterocyclyl is optionally substituted with R¹⁶; or when two of the    substituents of R⁹ are attached to the same atom, they may be taken    together to form a 4 to 7-membered saturated monocyclic heterocyclyl    containing at least one heteroatom selected from N, O or S;-   R¹⁰ and R¹¹ each independently represent hydrogen, C₁₋₆alkyl,    cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkyl    substituted with —C(═O)—NR¹⁴R¹⁵, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,    hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl wherein each    C₁₋₆alkyl may optionally be substituted with one or two hydroxyl    groups, R⁶, C₁₋₆alkyl substituted with R⁶, —C(═O)—R⁶,    —C(═O)—C₁₋₆alkyl, —C(═O)-hydroxyC₁₋₆alkyl, —C(═O)-haloC₁₋₆alkyl,    —C(═O)-hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with —Si(CH₃)₃,    —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl    substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,    C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl    substituted with —NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted    with —NH—S(═O)₂—NR¹⁴R¹⁵;-   R¹² represents hydrogen or C₁₋₄alkyl optionally substituted with    C₁₋₄alkoxy;-   R¹³ represents C₃₋₈cycloalkyl or a saturated 4 to 6-membered    monocyclic heterocyclyl containing at least one heteroatom selected    from N, O or S, wherein said C₃₋₈cycloalkyl or monocyclic    heterocyclyl is optionally substituted with 1, 2 or 3 substituents    each independently selected from halogen, hydroxyl, C₁₋₆alkyl,    —C(═O)—C₁₋₆alkyl, C₁₋₆alkoxy, or —NR¹⁴R¹⁵;-   R¹⁴ and R¹⁵ each independently represent hydrogen, or haloC₁₋₄alkyl,    or C₁₋₄alkyl optionally substituted with a substituent selected from    hydroxyl, C₁₋₄alkoxy, amino or mono- or di(C₁₋₄alkyl)amino;-   R¹⁶ represents hydroxyl, halogen, cyano, C₁₋₄alkyl, C₁₋₄alkoxy,    —NR¹⁴R¹⁵ or —C(═O)NR¹⁴R¹⁵;    the N-oxides thereof, the pharmaceutically acceptable salts thereof    or the solvates thereof.

In one embodiment there is provided a compound of formula (I⁰):

including any stereochemically isomeric form thereof, wherein

-   n represents an integer equal to 0, 1, 2, 3 or 4;-   R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl, hydroxyC₁₋₆alkyl,    haloC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may    optionally be substituted with one or two hydroxyl groups, C₁₋₆alkyl    substituted with —NR⁴R⁵, C₁₋₆alkyl substituted with —C(═O)—NR⁴R⁵,    —S(═O)₂—C₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with    —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl,    R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkyl substituted with    —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶, or C₁₋₆alkyl    substituted with —Si(CH₃)₃;-   each R² is independently selected from halogen, cyano, C₁₋₄alkyl,    C₂₋₄alkenyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl, hydroxyC₁₋₄alkoxy,    haloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, R¹³, C₁₋₄alkoxy substituted    with R¹³, —C(═O)—R¹³, C₁₋₄alkyl substituted with NR⁷R⁸, C₁₋₄alkoxy    substituted with NR⁷R⁸, —NR⁷R⁸ or —C(═O)—NR⁷R⁸;-   R³ represents C₁₋₆alkyl, hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,    haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl,    C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be    substituted with one or two hydroxy groups, C₁₋₆alkyl substituted    with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted    with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two    halogens and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with    —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,    C₁₋₆alkyl substituted with carboxyl, C₁₋₆alkyl substituted with    —O—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl,    C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl    substituted with hydroxyl and R⁹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹²,    C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted    with —C(═O)—R⁹, C₂₋₆alkynyl substituted with R⁹, hydroxyC₁₋₆alkoxy,    C₂₋₆alkenyl, C₂₋₆alkynyl, R¹³ or C₁₋₆alkyl substituted with    C₁₋₆alkoxyC₁₋₆alkyl-C(═O)—;-   R⁴ and R⁵ independently represent hydrogen, C₁₋₆alkyl,    hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,    C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be    substituted with one or two hydroxyl groups, —S(═O)₂—C₁₋₆alkyl,    —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with    —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,    C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted    with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with    —NH—S(═O)₂—NR¹⁴R¹⁴R¹⁵, R¹³ or C₁₋₆alkyl substituted with R¹³;-   R⁶ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4, 5, 6 or    7-membered monocyclic heterocyclyl containing at least one    heteroatom selected from N, O or S; said C₃₋₈cycloalkyl,    C₃₋₈cycloalkenyl, phenyl, 4, 5, 6 or 7-membered monocyclic    heterocyclyl, optionally and each independently being substituted by    1, 2, 3, 4 or 5 substituents, each substituent independently being    selected from cyano, C₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyl, carboxyl,    hydroxyC₁₋₆alkyl, halogen, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkyl-O—C(═O)—, —NR¹⁴R¹⁵,    —C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkyl    substituted with —C(═O)—NR¹⁴R¹⁵, —S(═O)₂—C₁₋₆alkyl,    —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with    —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,    C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted    with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted with    —NH—S(═O)₂—NR¹⁴R¹⁴R¹⁵;-   R⁷ and R⁸ independently represent hydrogen, C₁₋₆alkyl,    hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl or    C₁₋₆alkoxyC₁₋₆alkyl;-   R⁹ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl or a 3 to 12    membered monocyclic or bicyclic heterocyclyl containing at least one    heteroatom selected from N, O or S, said C₃₋₈cycloalkyl,    C₃₋₈cycloalkenyl, aryl or a 3 to 12 membered monocyclic or bicyclic    heterocyclyl each optionally and each independently being    substituted with 1 to 5 substituents, each substituent independently    being selected from ═OO, C₁₋₄alkyl, hydroxyl, carboxyl,    hydroxyC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, C₁₋₄alkyl-O—C(═O)—,    C₁₋₄alkyl substituted with C₁₋₆alkyl-O—C(═O)—, C₁₋₄alkyl-C(═O)—,    C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl may optionally be    substituted with one or two hydroxyl groups, halogen, haloC₁₋₄alkyl,    hydroxyhaloC₁₋₄alkyl, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkyl    substituted with —NR¹⁴R¹⁵, C₁₋₄alkyl substituted with    —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkoxy, —S(═O)₂—C₁₋₄alkyl,    —S(═O)₂-haloC₁₋₄alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with    —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with —NH—S(═O)₂—C₁₋₄alkyl,    C₁₋₄alkyl substituted with —NH—S(═O)₂-haloC₁₋₄alkyl, C₁₋₄alkyl    substituted with —NH—S(═O)₂—NR¹⁴R¹⁵, R¹³, —C(═O)—R¹³, C₁₋₄alkyl    substituted with R¹³, phenyl optionally substituted with R¹⁶,    phenylC₁₋₆alkyl wherein the phenyl is optionally substituted with    R¹⁶, a 5 or 6-membered aromatic monocyclic heterocyclyl containing    at least one heteroatom selected from N, O or S wherein said    heterocyclyl is optionally substituted with R¹⁶;    -   or when two of the substituents of R⁹ are attached to the same        atom, they may be taken together to form a 4, 5, 6 or 7-membered        saturated monocyclic heterocyclyl containing at least one        heteroatom selected from N, O or S;-   R¹⁰ and R¹¹ each independently represent hydrogen, C₁₋₆alkyl,    cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, haloC₁₋₆alkyl,    hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein    each C₁₋₆alkyl may optionally be substituted with one or two    hydroxyl groups, R⁶, C₁₋₆alkyl substituted with R⁶, —C(═O)—R⁶,    —C(═O)—C₁₋₆alkyl, —C(═O)-hydroxyC₁₋₆alkyl, —C(═O)-haloC₁₋₆alkyl,    —C(═O)-hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with —Si(CH₃)₃,    —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl    substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with    —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,    C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl    substituted with —NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted    with —NH—S(═O)₂—NR¹⁴R¹⁵;-   R¹² represents hydrogen or C₁₋₄alkyl optionally substituted with    C₁₋₄alkoxy;-   R¹³ represents C₃₋₈cycloalkyl or a saturated 4 to 6-membered    monocyclic heterocyclyl containing at least one heteroatom selected    from N, O or S, wherein said C₃₋₈cycloalkyl or monocyclic    heterocyclyl is optionally substituted with 1, 2 or 3 substituents    each independently selected from halogen, hydroxyl, C₁₋₆alkyl,    —(C═O)—C₁₋₆alkyl, C₁₋₆alkoxy, or —NR¹⁴R¹⁵;-   R¹⁴ and R¹⁵ each independently represent hydrogen, or haloC₁₋₄alkyl,    or C₁₋₄alkyl optionally substituted with a substituent selected from    hydroxyl, C₁₋₄alkoxy, amino or mono- or di(C₁₋₄alkyl)amino;-   R¹⁶ represents hydroxyl, halogen, cyano, C₁₋₄alkyl, C₁₋₄alkoxy,    —NR¹⁴R¹⁵ or —C(═O)NR¹⁴R¹⁵;    and a N-oxide thereof, a pharmaceutically acceptable salt thereof or    a solvate thereof.

In one embodiment there is provided a compound of formula (I⁰):

including any stereochemically isomeric form thereof, wherein

-   n represents an integer equal to 0, 1, 2, 3 or 4;-   R¹ represents hydrogen,-   C₁₋₆alkyl, for example —CH₃, —CD₃, —CH₂CH₃, —CH₂CH₂CH₃,    —CH₂CH(CH₃)₂, —CH(CH₃)₂, —CH₂CH(CH₃)₂, C₂₋₄alkenyl, for example    —CH₂—CH═CH₂, hydroxyC₁₋₆alkyl, for example —CH₂CH₂OH, —CH₂C(CH₃)₂OH    or CH₂CHOHCH₂OH, haloC₁₋₆alkyl, for example —CH₂CH₂F, CH₂CH₂CH₂C₁ or    CH₂CH₂Br,-   C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be    substituted with one or two hydroxyl groups, for example    —CH₂CH₂OCH₃,-   C₁₋₆alkyl substituted with —NR⁴R⁵, for example —CH₂CH₂NH₂ or    —CH₂CH₂CH₂NH₂, —CH₂CH₂NHCH₃, —CH₂CH₂NHS(═O)₂N(CH₃)₂,    —CH₂CH₂NHS(═O)₂CH₃,-   C₁₋₆alkyl substituted with —C(═O)—NR⁴R⁵, for example    —CH₂C(═O)N(CH₃)₂, —CH₂C(═O)NHCH₃ or —C(CH₃)₂C(═O)NHCH₃,    —C(CH₃)₂C(═O)NHCH₂CH₂OH or —CH₂C(═O)NHCH₂CH₂OH,    —CH₂C(═O)NHCH₂CH₂OCH₃ or —C(CH₃)₂C(═O)NHCH₂CH₂OCH₃,    —CH₂—C(═O)—NH—CH₂—CH₂— (pyrrolidin-1-yl),    —CH₂CH₂CH₂NHCH₂CH₂—S(═O)₂—CH₃, —S(═O)₂—C₁₋₆alkyl, for example    —S(═O)₂—CH₃,-   —S(═O)₂—NR¹⁴R¹⁵, for example —S(═O)₂—N(CH₃)₂,-   C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, for example    —CH₂CH₂S(═O)₂—CH₃,-   C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, for example    —CH₂CH₂NHS(═O)₂—CH₃,-   R⁶, for example 4-piperidinyl, 2-tetrahydropyranyl or    4-tetrahydropyranyl, 4-tetrahydrofuranyl, 3-azetidinyl substituted    in the 1 position by —CH₂CH₂OH, 4-piperidinyl substituted on the    nitrogen atom with (CH₃)₃C—O—C(═O)—, 4-piperidinyl substituted on    the nitrogen atom with —S(═O)₂CH₃, 4-piperidinyl substituted on the    nitrogen atom with —CH₃,-   C₁₋₆alkyl substituted with R⁶, for example methyl or ethyl each    substituted with 4-piperidinyl, 4-piperazinyl, 1-pyrrolidinyl or    4-tetrahydropyranyl; propyl substituted with morpholinyl where the    morpholinyl is linked to the propyl through the N heteroatom;    methyl, ethyl or propyl each substituted with 4-piperidinyl    substituted on the nitrogen atom with (CH₃)₃C—O—C(═O)—,    4-piperidinyl substituted on the nitrogen atom with —CH₃,    4-piperazinyl substituted on the nitrogen atom with    (CH₃)₃C—O—C(═O)—, 4-piperazinyl substituted on the nitrogen atom    with —CH₂CH₂OH, 4-piperazinyl substituted on the nitrogen atom with    —CH₂CH₂CH₂OH, 1-piperidinyl substituted in the 1 position by —OH,    1-piperidinyl substituted in the 1 position by —O—CH₃; methyl    substituted with 2-thiophenyl substituted in the 5 position with    chlorine; methyl substituted with 4-piperidinyl substituted on the    nitrogen atom with (CH₃)₃C—O—C(═O)— and in the 4 position by —OH,-   C₁₋₆alkyl substituted with —C(═O)—R⁶, for example    —C(CH₃)₂—C(═O)-(piperazin-4-yl), —C(CH₃)₂—C(═O)-(piperazin-4-yl)    substituted on the nitrogen atom in the 1 position by    (CH₃)₃C—O—C(═O)—, —CH₂—C(═O)-(pyrrolidin-1-yl) substituted in the 3    position by —OH,-   hydroxyC₁₋₆alkyl substituted with R⁶, for example —CH₂CHOHCH₂—    substituted with 1-piperidinyl,-   C₁₋₆alkyl substituted with —Si(CH₃)₃, for example —CH₂Si(CH₃)₃, or-   cyanoC₁₋₄alkyl, for example —CH₂CH₂CN;-   each R² is independently selected from-   hydroxyl,-   halogen, for example fluorine, chlorine or bromine,-   cyano,-   C₁₋₄alkyl, for example —CH₃,-   C₂₋₄alkenyl, for example —CH═CH₂,-   C₁₋₄alkoxy, for example CH₃O—, (CH₃)₂CHO—, CH₃CH₂O—, CD₃O—,-   hydroxyC₁₋₄alkyl, for example —CH₂OH,-   hydroxyC₁₋₄alkoxy, for example —OCH₂CH₂OH,-   haloC₁₋₄alkyl, for example —CF₃,-   haloC₁₋₄alkoxy, for example —OCH₂CH₂F, CHF₂O— or —OCF₃,-   C₁₋₄alkoxyC₁₋₄alkyl, for example —CH₂CH₂OCH₃,-   R¹³, for example 2-dioxolanyl,-   C₁₋₄alkoxy substituted with R¹³, for example —OCH₂C₃H₅,-   —C(═O)—R¹³, for example —C(═O)-(1-pyrrolidinyl),-   C₁₋₄alkyl substituted with NR⁷R⁸, for example —CH₂N(CH₂CH₃)₂,    —CH₂N(CH₃)₂ or —CH₂N(CH₂CH₃)(CH₃),-   C₁₋₄alkoxy substituted with NR⁷R⁸, for example —OCH₂CH₂NH₂,-   —NR⁷R⁸, for example —NHCH₃ or —N(CH₃)₂,-   —C(═O)—NR⁷R⁸; for example —C(═O)—NHCH₃, or-   two R² groups are attached to adjacent carbon atoms and together to    form a radical of formula —O—(C(R¹⁷)₂)_(p)—O— wherein R¹⁷ represents    hydrogen and p represents 1;-   R³ represents-   C₁₋₆alkyl, for example —CH₃, —CH₂CH₃, —CH₂CH₂CH₃ or —CH₂CH(CH₃)₂,    hydroxyC₁₋₆alkyl, for example —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CHOHCH₃,    —CH₂CHOHCH₂CH₃, —CH₂CHOHCH(CH₃)₂, —CH₂CH₂C(OH)(CH₃)₂, —CH₂CHOHCH₂OH,    —CH₂C(CH₃)₂OH, —CD₂CD₂OH, —CD₂CD₂CD₂OH, or —CH(CH₃)CH₂OH,-   hydroxyhaloC₁₋₆alkyl, for example —CH₂CHOHCF₃,-   haloC₁₋₆alkyl, for example —CH₂CH₂CH₂Cl, —CH₂CH₂CH₂CH₂Cl, —CH₂CH₂F    or —CH₂CH₂I,-   haloC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl, for    example —CH₂CH(CF₃)—O—C(═O)CH₃, hydroxyC₂₋₆alkynyl, for example    —CH₂—C≡C—CH₂OH or —CH₂—C≡C—C(CH₃)₂OH,-   C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl, for example    CH₃—C(═O)—CH₂—, (CH₃)₂CH—C(═O)—CH₂—,-   C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be    substituted with one or two hydroxy groups, for example —CH₂CH₂OCH₃,    —CH₂CH₂OCH₂CH₃ or —CH₂CHOHCH₂OCH₃,-   C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be    substituted with one or two hydroxyl groups or with    —O—C(═O)—C₁₋₆alkyl, for example —CH₂CH(—O—C(═O)CH₃)CH₂OCH₃,-   C₁₋₆alkyl substituted with R⁹, for example

—CH₂—C₃H₅ or —CH₂C₅H₉,

C₁₋₆alkyl substituted with cyclopropyl substituted by —CH₂OH,CH₃CH₂—O—C(═O)-4-pyridinyl,

methyl substituted with 5-isoxazolyl which is substituted in the 3position with —CH₃. or substituted with 3-isoxazolyl which issubstituted in the 5 position by —CH₃,

ethyl or propyl substituted by 4-morpholinyl, methyl substituted by3-morpholinyl, methyl substituted by 6-morpholinyl,

ethyl or propyl substituted by 4-morpholinyl which is substituted in the2 and 6 positions by —CH₃,

methyl substituted by 2-morpholinyl which is substituted in the 4position by —CH₂—C₆H₅ methyl substituted by 3-morpholinyl substituted inthe 5 position by two —CH₃, methyl substituted by 6-morpholinylsubstituted in the 4 position by —CH(CH₃)₂, methyl substituted by6-morpholinyl substituted in the 3 position by ═0 and 4 position by—CH(CH₃)₂, methyl substituted by 2-morpholinyl substituted in the 4positon by —CH₂—C₆H₅, methyl substituted with 2-tetrahydrofuranyl,2-dioxolane, ethylene oxide, 2-furanyl, or 4-tetrahydropyranyl,

methyl substituted with 3-oxetanyl which is substituted in the 3position by —CH₃, methyl substituted with 3-oxetanyl substituted in the3 position by —CH₂NHCH(CH₃)₂,

methyl substituted with 3-pyridinyl or 2-pyrazinyl or propyl substitutedwith 4-pyridinyl

methyl or propyl substituted with 2-pyrimidinyl,

methyl substituted with 3-pyridinyl which is substituted in the 6position by chlorine or methyl substituted with 2-pyridinyl which issubstituted in the 6 position by bromine,

propyl substituted with 6-pyridinyl substituted in the 4 position by—CH₃, propyl substituted with 6-pyridinyl substituted in the 3 positionby —OCH₃, methyl substituted with 2-pyridinyl substituted in the 6position by —OCH₃, methyl substituted with 6-pyridinyl substituted inthe 2 position by —CH₂NH₂, methyl substituted with 6-pyridinylsubstituted in the 2 position by —NHCH₃,

propyl substituted with 2-pyrimidinyl substituted in the 4 position by—OCH₃, methyl substituted with 2-pyrimidinyl substituted in the 4 and 6positions by —OCH₃, propyl substituted with 2-pyrimidinyl substituted inthe 4 position by —OH,

methyl substituted with 3-piperazinyl,

ethyl substituted with 1-piperazinyl which is substituted in the 4position by 4-piperidinyl being substituted in the 1 position by—C(═O)—CH₃, ethyl substituted with 1-piperazinyl substituted in the 4position with —CH₂C(═O)NHCH(CH₃)₂,

ethyl or propyl substituted with 1,2,3,6-tetrahydropyridine,

C₁₋₆alkyl substituted with azetidinyl,

propyl substituted by 1-azetidinyl which is substituted in the 3position by two fluorines,

propyl substituted by 1-azetidinyl which is substituted in the 3position by one —OH,

ethyl or propyl substituted with 1-pyrrolidinyl or 2-pyrrolidinyl,

propyl substituted with 1-pyrrolidinyl which is substituted in the 3position by two fluorines or propyl substituted with 1-pyrrolidinylwhich is substituted in the 3 position by one fluorine,

propyl substituted with 1-pyrrolidinyl which is substituted in the 2position by —CH₂Cl,

ethyl or propyl substituted with 1-pyrrolidinyl which is substituted inthe 3 position by —OH,

ethyl or propyl substituted with 1-pyrrolidinyl which is substituted inthe 2 position by ═O,

propyl substituted with 1-pyrrolidinyl which is substituted in the 3position by —S(═O)₂—CH₃,

ethyl or propyl substituted with 1-pyrrolidinyl which is substituted inthe 3 position with —NH₂,

ethyl substituted with 1-pyrrolidinyl which is substituted in the 3position with —N(CH₃)₂, propyl substituted with 1-pyrrolidinyl which issubstituted in the 3 position with —NHCH₃,

ethyl or propyl substituted with a) 1-pyrrolidinyl which is substitutedin the 2 position with —CH₃; b) 1-pyrrolidinyl which is substituted inthe 2 and the 5 position with —CH₃; or c) 1-pyrrolidinyl which issubstituted in the 2 position with two —CH₃,

ethyl substituted with 1-pyrrolidinyl which is substituted in the 2position with —C(═O)OH,

ethyl or propyl substituted with 1-pyrrolidinyl which is substituted inthe 2 position by —CH₂OH or with pyrrolidinyl which is substituted with—C(CH₃)₂OH or —CH₂CH₂OH,

propyl substituted with a) 1-pyrrolidinyl which is substituted in the 3position by 1-piperidinyl, or b) 1-pyrrolidinyl which is substituted inthe 3 position by 4-morpholinyl being substituted in positions 2 and 6by —CH₃,

ethyl or propyl substituted with 1-pyrrolidinyl which is substituted inthe 3 position by —CN,

propyl substituted with 1-pyrrolidinyl which is substituted in the 2position by —CH₂CN, or ethyl substituted with 1-pyrrolidinyl substitutedin the 2 position by —CH₂CN,

propyl substituted with 1-pyrrolidinyl which is substituted in the 2position by —CH₂NH—S(═O)₂—CF₃,

methyl or ethyl substituted by a) 2-pyrrolidinyl which is substituted inthe 1 position by (CH₃)₃C—O—C(═O)— or b) 1-pyrrolidinyl which issubstituted in the 2 position by CH₃—O—C(═O)—, methyl substituted by3-pyrrolidinyl substituted in the 1-position by 2-pyridinyl substitutedin the 3-position by —OCH₃ or methyl substituted by 3-pyrrolidinylsubstituted in the 1-position by 2-pyrimidinyl substituted in the4-position by —OCH₃,

methyl, ethyl or propyl substituted by 4-piperidinyl or 1-piperidinyl,

ethyl substituted by 1-piperidinyl which is substituted at the 4position by two fluorines,

methyl or ethyl substituted by a) 1-piperidinyl which is substituted atthe 4 position by one —OH or b) 4-piperidinyl which is substituted atthe 4 position by one —OH,

ethyl substituted by 1-piperidinyl which is substituted at the 3position or the 4 position by —NH₂,

ethyl substituted by 1-piperidinyl which is substituted at the 4position by —N(CH₃)₂,

methyl, ethyl or propyl substituted by a) 1-piperidinyl which issubstituted at the 2 position by —CH₃, b) 1-piperidinyl which issubstituted at the 2 and the 6 position by —CH₃, c) 4-piperidinyl whichis substituted at the 1 position by —CH(CH₃)₂, d) 4-piperidinyl which issubstituted at the 1 position by —CH₃, e) 1-piperidinyl which issubstituted at the 3 and the 5 position by —CH₃,

ethyl substituted by a) 1-piperidinyl which is substituted in the 4position by —C(CH₃)₂OH, b) 1-piperidinyl which is substituted in the 4position by —CH₂CH₂OH, c) 1-piperidinyl which is substituted in the 4position by —CH₂OH,

ethyl or propyl substituted with 1-piperidinyl which is substituted atthe 3 position with —CN,

methyl or ethyl substituted with a) 1-piperidinyl which is substitutedin the 4 position by CH₃CH₂—O—C(═O)—, or b) 4-piperidinyl which issubstituted in the 1 position by (CH₃)₃C—O—C(═O)—,

methyl substituted with 4-piperidinyl which is substituted in the 4position by —OH and in the 1 position by (CH₃)₃C—O—C(═O)—,

methyl substituted with 4-piperidinyl which is substituted in the 4position by —OCH₃ and in the 1 position by (CH₃)₃C—O—C(═O)—,

methyl or ethyl substituted with a) 1-piperidinyl which is substitutedin the 4 position by —OCH₃ or b) 4-piperidinyl which is substituted inthe 4 position by —OCH₃,

propyl substituted with 1-piperidinyl which is substituted in the 4position by —CF₃,

ethyl substituted withl-piperidinyl which is substituted in the 3position by —C(═O)—NH₂, ethyl or propyl substituted with 1-piperidinylsubstituted in the 2 position by —C(═O)—NH₂, ethyl substituted by1-piperidinyl substituted at the 4 position by ═O, or propyl substitutedby 1-piperidinyl substituted at the 2 position by ═O,

ethyl substituted with 1-piperidinyl substituted in the 4 position by—CH₂NH₂,

methyl substituted by 4-piperidinyl substituted in the 1-position by2-pyrimidinyl substituted in the 4-position by —OCH₃,

ethyl, propyl or butyl substituted with isoindole-1,3-dione,—CH(CH₃)CH₂-substituted with isoindolyl-1,3,-dione,

ethyl substituted with 2-oxa-6-aza-spiro[3.3.]heptane,

ethyl substituted with 1,4-dioxa-8-aza-spiro[4.5]decane,

methyl substituted with 2-thiophenyl,

methyl substituted with 2-thiophenyl which is substituted at the 5position by chlorine,

methyl substituted with 4-thiazolyl which is substituted in the 2position by —CH₃,

ethyl or propyl substituted with 1-piperazinyl,

ethyl substituted with 1-piperazinyl which is substituted in the 4position by CH₃—C(═O)—,

ethyl substituted with 1-piperazinyl which is substituted in the 4position by —CH₂CH₂OH,

ethyl or propyl substituted with a) 1-piperazinyl which is substitutedat the 3 and 5 positions by —CH₃ or b) 1-piperazinyl which issubstituted at the 4 position by —CH₃,

ethyl substituted with 1-piperazinyl which is substituted in the 3position by ═O,

ethyl substituted with 1-piperazinyl which is substituted in the 4position by —C(═O)—C₃H₅,

methyl substituted with 2-piperazinyl substituted in the 1 and 4position by methylphenyl wherein the phenyl is substituted in the 4position by CH₃O—, ethyl substituted with 5-tetrazolyl,

methyl substituted with a) 2-(1,3,4-oxadiazoyl) which is substituted atthe 5 position by —NH₂ or b) 2-(1,3,4-oxadiazolyl) which is substitutedat the 5 position by —NH—CH₂CH₂OH,

methyl, ethyl or propyl substituted with 1-pyrazolyl or 2-imidazolyl,methyl substituted with 3-pyrazolyl or 5-pyrazolyl,

methyl, ethyl or propyl substituted with a) 1-imidazolyl which issubstituted at the 2 position by —CH₃, b) 3-pyrazolyl which issubstituted at the 1 and 5 positions by —CH₃, c) 1-imidazolyl which issubstituted at the 2 and 5 positions by —CH₃, d) 1-imidazolyl which issubstituted at the 2 and 4 positions by —CH₃, e) 2-imidazolyl which issubstituted at the 1 position by —CH₃ or f) 2-imidazolyl which issubstituted at the 1 position by —CH₂CH₃, methyl substituted with2-imidazolyl substituted at the 5 position by —CH₃ ethyl substitutedwith 1-pyrazolyl substituted at the 3 position by —CH₃

methyl substituted with 4-pyrazolyl substituted at the 1 position by—CH₃-methyl substituted with 2-imidazolyl substituted in the 3 positionby —S(═O)₂—N(CH₃)₂ and in the 5 position by —CH₃, methyl substitutedwith 5-pyrazolyl substituted in the 2 position by 2-tetrahydropyran, ormethyl substituted with 3-pyrazolyl substituted in the 1 position by2-tetrahydropyran methyl substituted with 2-imidazolyl which issubstituted in the 1 position by —S(═O)₂—N(CH₃)₂,

methyl substituted with 4-(1,2,3-triazolyl),

methyl substituted with a) 4-(1,2,3-triazolyl) which is substituted inthe 1 position by —CH₂CH₂OH or b) 4-(1,2,3-triazolyl) which issubstituted in the 2 position by —CH₂OH,

methyl substituted with 4-(1,2,3-triazolyl) which is substituted in the1 position by —CH₂C(═O)—OCH₂CH₃,

ethyl substituted with 1-(1,2,4-triazolyl,

ethyl or propyl substituted with 1-(1,2,4-triazolyl) substituted in the3 position by —CH₃,

ethyl or propyl substituted with 2-(1,2,4-triazolyl) substituted in the3 position by —CH₃,

ethyl or propyl substituted with 3-oxazolidinyl which is substituted inthe 2 position by ═O, methyl substituted with 5-oxazolidinyl substitutedin the 2 position by ═O, methyl substituted with 5-oxazolidinylsubstituted in the 2 position by ═O and in the 3 position by —CH(CH₃)₂,

propyl substituted with 4-thiomorpholinyl which is substituted in the 1position by two ═O groups,

ethyl substituted with 1-homopiperazinyl,

ethyl substituted with homomorpholinyl,

—CH₂—C₆H₅,

methyl substituted with phenyl which is substituted in the 2, 3 or 4position by chlorine, cyanoC₁₋₆alkyl, for example —CH₂CH₂CN or—CH₂CH₂CH₂CN, C₁₋₆alkyl substituted with —NR¹¹R¹¹, for example—CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂, —CH₂CH(CH₃)NH₂,—CH(CH₃)CH₂NH₂, —CH₂CH₂NHCH₃, —CH₂CH₂CH₂NHCH₃, —CH₂CH₂NHCH₂CH₃,—CH₂CH₂NHCH(CH₃)₂, —CD₂-CD₂-NHCH(CH₃)₂, —CH₂CH₂CH₂NHCH(CH₃)₂,—CH(CH₃)CH₂NHCH(CH₃)₂, —CH₂CH₂N(CH₂CH₃)₂, —CH₂CH₂N(CH₂CH₃)(CH(CH₃)₂),—CH₂CH₂N(CH₃)₂ or —CH₂CH₂N(CH₃)CH(CH₃)₂, —CH₂CH₂CH₂NHCH₂CF₃,—CH₂CH₂NHCH₂CHF₂ or —CH₂CH₂NHCH₂CH₂F, —CH(CH₃)CH₂NHCH₂CF₃,—CH₂CH(CH₃)NHCH₂CF₃, —CH₂CH₂NHCH₂CF₃,—CH₂CH₂CH₂NHCH₂CHF₂—CH₂CH₂NHCH₂CH₂CF₃, —CH₂CH₂CH₂NHCH₂CHF₂,—CH₂CH₂CH₂NHC(CH₃)₂CH₂F, —CD₂-CD₂-CD₂-NHCH₂CF₃, —CH₂CH₂NH—C(═O)—CH₃,—CH₂CH₂NH—S(═O)₂—CH₃, —CH₂CH₂CH₂NH—S(═O)₂—CH₃, —CH₂CH₂NH—S(═O)₂—CH₂CH₃or —CH₂CH₂NH—S(═O)₂—CH(CH₃)₂, —CH₂CH₂NH—S(═O)₂—N(CH₃)₂ or—CH₂CH₂CH₂NH—S(═O)₂—N(CH₃)₂, —CH₂CH₂NHCH₂CH₂OH,—CH₂CH₂CH₂NH—C(═O)—C(OH)(CH₃)CF₃ or —CH₂CH₂NH—C(═O)—C(OH)(CH₃)CF₃,—CH₂CH₂NH—C(═O)—C₃H₅, —CH₂CH₂NH—C(═O)-(piperidin-3-yl) where thepiperidinyl is substituted at the 1 position by —CH₃,

-   —CH₂CH₂NHCH₂CH₂CN, —CH₂CH₂CH₂NHCH₂CH₂CN, —CH₂CH₂NHC₃H₅,    —CH₂CH₂NHC₅H₉ or —CH₂CH₂NH-(2,2,6,6-tetramethyl-piperidin-4-yl),-   —CH₂CH₂NH-(piperidin-4-yl) where the piperidinyl is substituted in    the 1 position by —S(═O)₂NH₂,-   —CH₂CH₂NHCH₂C₃H₅, —CH₂CH₂NHCH₂— (tetrahydrofuran-2-yl),    —CH₂CH₂NHCH₂-(pyridin-6-yl),-   —CH₂CH₂NHC(═O)—CF₃ or —CH₂CH₂CH₂NHC(═O)—CF₃;-   —CH₂CH₂NHCH₂Si(CH₃)₃,-   —CH₂CH₂N(CH₃)CH₂—C₆H₅,-   one of R¹⁰ and R¹¹ represents —CH(CH₃)₂ and the other represents    —CH₂—C₆H₅ wherein the phenyl is substituted in the 4-position by    —NH₂,-   —CH₂CH₂N(CH(CH₃)₂)CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHCH₂C(═O)NH₂ or    —CH₂CH₂NHCH₂C(═O)NH₂,-   —CH₂CH₂CH₂N(CH₃)—OCH₃,-   —CH₂CH₂NH—OCH₃, or-   —CH₂CH₂NHCH₂CHOHCF₃; —CH₂CH₂CH₂NHCOOH.-   C₁₋₆alkyl substituted with hydroxyl and —NR¹⁰R¹¹, for example    —CH₂CHOHCH₂NH₂, —CH₂CHOHCH₂NHCH₃ or —CH₂CHOHCH₂NHCH(CH₃)₂,    —CH₂CHOHCH₂NHCH₂CF₃, —CH₂CHOHCH₂N(CH(CH₃)₂)—C(═O)CH₂Cl,-   C₁₋₆alkyl substituted with one or two halogens and —NR¹⁰R¹¹, for    example —CH₂CHFCH₂NH₂,-   C₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl, for example    —CH₂—C(═O)—O—CH₂CH₃ or —CH₂CH₂—C(═O)—O—CH₂CH₃,    —CH(CH₃)C(═O)—O—CH₂CH₃,-   C₁₋₆alkyl (for example methyl) substituted with    C₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, for example —CH₂—C(═O)—CH₂OCH₃,-   C₁₋₆alkyl substituted with —O—C(═O)—NR¹¹R¹¹, for example    —CH₂—C(═O)NH₂, —CH₂—C(═O)NHCH₃, —CH₂C(═O)NHCH(CH₃)₂ or    —CH₂CH₂C(═O)NHCH(CH₃)₂, —CH₂—C(═O)—NHCH₂CH₂OCH₃,    —CH₂—C(═O)—NH—CH₂CH₂— (pyrrolidin-1-yl) or —CH₂—C(═O)—NH—CH₂CH₂—    (imidazol-2-yl), —CH₂—C(═O)—NHCH₂CH₂OH, —CH₂—C(═O)—NHCH₂CH₂NH₂,    —CH₂CH₂C(═O)—NHCH₂CF₃—CH₂CH₂C(═O)N(CH₃)—OCH₃,    —CH₂C(═O)NH-(pyridin-2-yl) wherein the pyridin-2-Y1 is substituted    in the 3-position by —OCH₃, —CH₂C(═O)NH-(pyridin-6-yl) wherein the    pyridin-6-Y1 is substituted in the 4-position by —CH₃ or    —CH₂C(═O)NH-(pyrimidin-2-yl) wherein the pyrimidin-2-Y1 is    substituted in the 4-position by —OCH₃, —CH₂C(═O)NH-(pyridin-3-yl),    —CH₂C(═O)NH-(pyridin-6-yl) or —CH₂C(═O)NH-(pyridin-4-yl),-   C₁₋₆alkyl substituted with carboxyl, for example —CH₂C(═O)OH or    —CH₂CH₂C(═O)OH,-   C₁₋₆alkyl substituted with —O—C(═O)—NR¹¹R¹¹, for example    —CH₂CH₂—O—C(═O)—NHCH₃,-   C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, for example    —CH₂CH₂NH—S(═O)₂—CH₃, CH₂CH₂CH₂NH—S(═O)₂—CH₃,    —CH₂CH₂NH—S(═O)₂—CH(CH₃)₂ or —CH₂CH₂NH—S(═O)₂—CH₂CH₃,-   C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—NR¹⁴R¹⁵, for example    —CH₂CH₂NH—S(═O)₂—N(CH₃)₂ or —CH₂CH₂CH₂NH—S(═O)₂—N(CH₃)₂,-   C₁₋₆alkyl substituted with R⁹ and optionally substituted with    —O—C(═O)—C₁₋₆alkyl, R⁹ represents 1H-pyrrolo[3,2-b]pyridinyl,    1-methyl-1H-pyrrolo[3,2-b]pyridinyl or furo[3,2-b]pyridinyl,-   C₁₋₆alkyl substituted with hydroxyl and R⁹, for example-   propyl substituted with —OH and 1-pyrrolidinyl,-   propyl substituted with —OH and 1-pyrrolidinyl where the    1-pyrrolidinyl is substituted at the 3 position by two fluorines,-   propyl substituted with —OH and 1-pyrrolidinyl where the    1-pyrrolidinyl is substituted at the 3 position by a cyano group,-   propyl substituted with —OH and 4-morpholinyl, propyl substituted    with —OH and 1-piperidinyl,-   propyl substituted with —OH and 2-(1,2,4-triazolyl) substituted in    the 3 position by —CH₃,-   propyl substituted with —OH and 1-imidazolyl substituted in the 2    position by —CH₃,-   propyl substituted with —OH and isoindole-1,3-dione,-   —C₁₋₆alkyl-C(R¹²)═N—O—R¹², for example —CH₂C(CH₃)═N—O—H,    —CH₂C(CH₂OCH₃)═N—O—H or —CH₂C(CH(CH₃)₂)═N—O—H—S(═O)₂—NR¹⁴R¹⁵, for    example —S(═O)₂—N(CH₃)₂, C₁₋₆alkyl substituted with    —S(═O)₂—C₁₋₆alkyl, for example —CH₂CH₂—S(═O)₂—CH₃,-   C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, for example    -   —CH₂C(═O)NH₂,    -   —CH₂C(═O)NHCH₃,    -   —CH₂C(═O)—NHCH₂CH₂OCH₃,    -   —CH₂C(═O)—NH—CH₂CH₂— (pyrrolidin-1-yl) or —CH₂C(═O)—NH—CH₂CH₂—        (imidazol-2-yl), —CH₂C(═O)—NHCH₂CH₂OH, —CH₂C(═O)—NHCH₂CH₂NH₂,-   C₁₋₆alkyl substituted with —C(═O)—R⁹, for example —CH₂C(═O)—R⁹ and    R⁹ is 1-pyrrolidinyl,-   C₂₋₆alkenyl substituted with R⁹, for example    —CH₂CH═CH-(2-pyrimidinyl), —CH₂CH═CH-(2-pyrimidinyl) wherein the    2-pyrimidinyl is substituted in the 4-position by —OCH₃,    —CH₂CH═CH-(2-pyridinyl) wherein the 2-pyridinyl is substituted in    the 4-position by —CH₃ or —CH₂CH═CH-(2-pyridinyl) wherein the    2-pyridinyl is substituted in the 3-position by —OCH₃,-   C₂₋₆alkynyl substituted with R⁹, for example-   —CH₂—C≡C— (2-imidazolyl) wherein the 2-imidazolyl is substituted in    the 1 position by —CH₃ or —CH₂—C≡C— (5-imidazolyl) wherein the    5-imidazolyl is substituted in the 1 position by —CH₃, —CH₂—C≡C—    (4-pyridinyl), —CH₂—C≡C— (3-pyridinyl), —CH₂—C≡C— (2-pyridinyl),    —CH₂—C≡C— (2-pyrimidinyl), —CH₂—C≡C— (6-pyrazinyl), —CH₂—C≡C—    (6-pyridinyl) substituted in the 2 or 4-position with —CH₂OH,    —CH₂—C≡C— (4-pyridinyl) substituted in the 6-position with —OCH₃,    —CH₂—C≡C— (2-pyridinyl) substituted in the 3 or 5-position with    —OCH₃, —CH₂—C≡C— (2-pyrimidinyl) substituted in the 4 or 6-position    with —OCH₃, —CH₂—C≡C— (6-pyridinyl) substituted in the 2, 4 or    5-position with —OCH₃, —CH₂—C≡C— (6-pyrimidinyl) substituted in the    4-position with —OCH₃, —CH₂—C≡C— (5-pyrazinyl) substituted in the    6-position with —OCH₃, —CH₂—C≡C— (2-pyrimidinyl) substituted in the    6-position with —OCH₂CH₃, —C(CH₃)₂—C≡C— (2-pyrimidinyl) substituted    in the 4-position with —OCH₃, —CH₂—C≡C— (2-pyrimidinyl) substituted    in the 4-position with —OCH(CH₃)₂; —CH₂—C≡C— (6-pyridinyl)    substituted in the 2 or the 4-position with cyano, —CH₂—C≡C—    (4-pyridinyl) substituted in the 5 or 6-position with cyano;    —CH₂—C≡C— (6-pyridinyl) substituted in the 2 or 4-position with    —NH₂, —CH₂—C≡C— (6-pyrimidinyl) substituted in the 2-position with    —NH₂, —CH₂—C≡C— (2-pyridinyl) substituted in the 3-position with    —NH₂, —CH₂—C≡C— (3-pyrazinyl) substituted in the 6-position with    —NH₂, —CH₂—C≡C— (6-pyridinyl) substituted in the 5-position with    —NHCH₃, —CH₂—C≡C— (6-pyridinyl) substituted in the 3 or 4-position    with —CH₃, —CH₂—C≡C— (2-pyridinyl) substituted in the 3-position    with —CH₃, —CH₂—C≡C— (2-pyrimidinyl) substituted in the 4-position    with —CH₃, —CH₂—C≡C— (2-pyrimidinyl) substituted in the 6-position    with —CH₂CH₃, —CH₂—C≡C— (6-pyrimidinyl) substituted in the    2-position with —CH₃ and in the 4-position with —NH₂, —CH₂—C≡C—    (6-pyrimidinyl) substituted in the 2-position with —NH₂ and in the    4-position with —Cl, —CH₂—C≡C— (2-pyrazinyl) substituted in the    3-position with —Cl, —CH₂—C≡C— (3-pyrazinyl) substituted in the    5-position with —CI, —CH₂—C≡C— (2-pyridinyl) substituted in the    3-position with —F, —CH₂—CC— (5-pyridinyl) substituted in the    6-position with —Br;-   —CH₂—C≡C— (6-pyridinyl) substituted in the 4-position with    —C(═O)—NH₂;-   —CH₂—C≡C— (6-pyridinyl) substituted in the 5-position with    CH₃—O—C(═O)—, —CH₂—C≡C— (2-pyrimidinyl) substituted in the    6-position with CH₃—O—C(═O)—;-   —CH₂—C≡C— (2-pyridinyl) substituted in the 3-position with —CF₃,    —CH₂—C≡C— (5-thiazolyl), —CH₂—C≡C— (phenyl), —CH₂—C≡C— (phenyl)    where the phenyl is substituted in the 5-position by —OCH₃,    —CH₂—C≡C— (3-azetidinyl) substituted in the 1-position by    C(CH₃)₃—O—C(═O)— and in the 3-position by —OH, —CH₂—C≡C—    (3-azetidinyl) substituted in the 3-position by —OH, —CH₂—C≡C—    (3-pyrrolidinyl) substituted in the 1-position by C(CH₃)₃—O—C(═O)—    and in the 3-position by —OH, —CH₂—C≡C— (3-pyrrolidinyl) substituted    in the 3-position by —OH, —CH₂—C≡C— (4-piperidinyl), —CH₂—C≡C—    (4-piperidinyl) substituted in the 4-position by —OH, —CH₂—C≡C—    (4-piperidinyl) substituted in the 1-position by C(CH₃)₃—O—C(═O)—,    —CH₂—C≡C— (4-tetrahydrofuranyl) substituted in the 3-position by    —OH, —CH₂—C≡C— (4-tetrahydropyranyl) substituted in the 4-position    by —OH, —CH₂—C≡C— (cyclohexyl),-   C₁₋₆alkyl substituted with R⁹, R⁹ represents a 6 to 8 membered    bridged heterocyclyl group, for example    2,5-diaza-bicyclo[2.2.1]heptanyl optionally substituted by    —C(═O)—O—C₄alkyl, C₁₋₆alkyloxyC₁₋₆alkyl wherein each C₁₋₆alkyl may    optionally be substituted with one or two hydroxyl groups, for    example —CH₂CHOHCH₂OCH₃,-   C₂₋₆alkenyl, for example —CH₂—CH═CH₂,-   C₂₋₆alkynyl, for example —CH₂—C≡C—H or —C(CH₃)₂—C≡C—H,-   C₁₋₆alkyl substituted with C₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, for example    —CH₂—C(═O)—CH₂OCH₃, or-   R¹³, for example 3-oxetanyl, cyclohexanyl substituted in the 4    position by —NH—CH(CH₃)₂,-   C₁₋₆alkyl substituted by R⁹, wherein R⁹ is a saturated heterocyclyl    substituted by R¹³, wherein R¹³ is a saturated heterocyclyl which is    optionally substituted, for example substituted by —C(═O)—C₁₋₆alkyl.    In one embodiment R⁹ is piperazinyl substituted by R¹³ wherein R¹³    is piperidinyl substituted by —C(═O)—C₁₋₆alkyl,-   C₁₋₆alkyl substituted by R⁹, wherein R⁹ is a saturated heterocyclyl    substituted by R¹³ wherein R¹³ is a saturated heterocyclyl which is    optionally substituted, for example substituted by —C(═O)—C₁₋₆alkyl.    In one embodiment R⁹ is piperazinyl substituted by R¹³ wherein R¹³    is piperidinyl substituted by —C(═O)—C₁₋₆alkyl.

In one embodiment there is provided a compound of formula (I⁰):

including any stereochemically isomeric form thereof, wherein

-   n represents an integer equal to 0, 1, 2, or 3;-   R¹ represents hydrogen,-   C₁₋₆alkyl, for example —CH₃, —CD₃, —CH₂CH₃, —CH₂CH₂CH₃,    —CH₂CH(CH₃)₂, —CH(CH₃)₂, —CH₂CH(CH₃)₂,-   C₂₋₄alkenyl, for example —CH₂—CH═CH₂,-   hydroxyC₁₋₆alkyl, for example —CH₂CH₂OH, —CH₂C(CH₃)₂OH or    CH₂CHOHCH₂OH, haloC₁₋₆alkyl, for example —CH₂CH₂F, CH₂CH₂CH₂C₁ or    CH₂CH₂Br,-   C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be    substituted with one or two hydroxyl groups, for example    —CH₂CH₂OCH₃,-   C₁₋₆alkyl substituted with —NR⁴R⁵, for example —CH₂CH₂NH₂ or    —CH₂CH₂CH₂NH₂, —CH₂CH₂NHCH₃, —CH₂CH₂NHS(═O)₂N(CH₃)₂,    —CH₂CH₂NHS(═O)₂N(CH₃)₂,-   C₁₋₆alkyl substituted with —C(═O)—NR⁴R⁵, for example    —CH₂C(═O)N(CH₃)₂, —CH₂C(═O)NHCH₃ or    —C(CH₃)₂C(═O)NHCH₃—C(CH₃)₂C(═O)NHCH₂CH₂OH or —CH₂C(═O)NHCH₂CH₂OH,    —CH₂C(═O)NHCH₂CH₂OCH₃ or —C(CH₃)₂C(═O)NHCH₂CH₂OCH₃,    —CH₂—C(═O)—NH—CH₂—CH₂— (pyrrolidin-1-yl),    —CH₂CH₂CH₂NHCH₂CH₂—S(═O)₂—CH₃,-   —S(═O)₂—C₁₋₆alkyl, for example —S(═O)₂—CH₃, —S(═O)₂—NR¹⁴R¹⁵, for    example —S(═O)₂—N(CH₃)₂,-   C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, for example    —CH₂CH₂S(═O)₂—CH₃,-   C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, for example    —CH₂CH₂NHS(═O)₂—CH₃, R⁶, for example 2-tetrahydropyranyl,    3-azetidinyl substituted in the 1 position by —CH₂CH₂OH,    4-piperidinyl substituted on the nitrogen atom with    (CH₃)₃C—O—C(═O)—, 4-piperidinyl substituted on the nitrogen atom    with —S(═O)₂CH₃,-   C₁₋₆alkyl substituted with R⁶, for example methyl or ethyl each    substituted with 4-piperidinyl, 4-piperazinyl, 1-pyrrolidinyl or    4-tetrahydropyranyl; propyl substituted with morpholinyl where the    morpholinyl is linked to the propyl through the N heteroatom;    methyl, ethyl or propyl each substituted with 4-piperidinyl    substituted on the nitrogen atom with (CH₃)₃C—O—C(═O)—,    4-piperidinyl substituted on the nitrogen atom with —CH₃,    4-piperazinyl substituted on the nitrogen atom with    (CH₃)₃C—O—C(═O)—, 4-piperazinyl substituted on the nitrogen atom    with —CH₂CH₂OH, 4-piperazinyl substituted on the nitrogen atom with    —CH₂CH₂CH₂OH, 1-piperidinyl substituted in the 1 position by —OH,    1-piperidinyl substituted in the 1 position by —O—CH₃; methyl    substituted with 2-thiophenyl substituted in the 5 position with    chlorine; methyl substituted with 4-piperidinyl substituted on the    nitrogen atom with (CH₃)₃C—O—C(═O)— and in the 4 position by —OH,-   C₁₋₆alkyl substituted with —C(═O)—R⁶, for example    —C(CH₃)₂—C(═O)-(piperazin-4-yl), —C(CH₃)₂—C(═O)-(piperazin-4-yl)    substituted on the nitrogen atom in the 1 position by    C(CH₃)₃—O—C(═O)—, —CH₂—C(═O)-(pyrrolidin-1-yl) substituted in the 3    position by —OH,-   hydroxyC₁₋₆alkyl substituted with R⁶, for example —CH₂CHOHCH₂—    substituted with 1-piperidinyl; or-   C₁₋₆alkyl substituted with —Si(CH₃)₃, for example —CH₂Si(CH₃)₃;-   each R² is independently selected from halogen, for example    fluorine, chlorine or bromine,-   cyano,-   C₁₋₄alkyl, for example —CH₃,-   C₂₋₄alkenyl, for example —CH═CH₂,-   C₁₋₄alkoxy, for example CH₃O—, (CH₃)₂CHO—, CH₃CH₂O—, CD₃O—,-   hydroxyC₁₋₄alkyl, for example —CH₂OH,-   hydroxyC₁₋₄alkoxy, for example —OCH₂CH₂OH,-   haloC₁₋₄alkoxy, for example —OCH₂CH₂F or CHF₂O—,-   C₁₋₄alkoxyC₁₋₄alkyl, for example —CH₂CH₂OCH₃, R¹³, for example    2-dioxolanyl,-   C₁₋₄alkoxy substituted with R¹³, for example —OCH₂C₃H₅, —C(═O)—R¹³,    for example —C(═O)-(1-pyrrolidinyl),-   C₁₋₄alkyl substituted with NR⁷R⁸, for example —CH₂N(CH₂CH₃)₂,    —CH₂N(CH₃)₂ or —CH₂N(CH₂CH₃)(CH₃),-   C₁₋₄alkoxy substituted with NR⁷R⁸, for example —OCH₂CH₂NH₂, —NR⁷R⁸,    for example —NHCH₃, or-   —C(═O)—NR⁷R⁸; for example —C(═O)—NHCH₃;-   R³ represents-   C₁₋₆alkyl, for example —CH₃, —CH₂CH₃, —CH₂CH₂CH₃ or —CH₂CH(CH₃)₂,-   hydroxyC₁₋₆alkyl, for example —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CHOHCH₃,    —CH₂CHOHCH₂CH₃, —CH₂CHOHCH(CH₃)₂, —CH₂CH₂C(OH)(CH₃)₂, —CH₂CHOHCH₂OH    or —CH₂C(CH₃)₂OH,-   hydroxyhaloC₁₋₆alkyl, for example —CH₂CHOHCF₃,-   haloC₁₋₆alkyl, for example —CH₂CH₂CH₂Cl or —CH₂CH₂CH₂CH₂C₁,-   C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl, for example    CH₃—C(═O)—CH₂—, (CH₃)₂CH—C(═O)—CH₂—,-   C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be    substituted with one or two hydroxy groups, for example —CH₂CH₂OCH₃,    —CH₂CH₂OCH₂CH₃ or —CH₂CHOHCH₂OCH₃,-   C₁₋₆alkyl substituted with R⁹, for example —CH₂—C₃H₅ or —CH₂C₅H₉,-   C₁₋₆alkyl substituted with cyclopropyl substituted by —CH₂OH or    CH₃CH₂—O—C(═O)-methyl substituted with 5-isoxazoyl which is    substituted in the 3 position with —CH₃.-   or substituted with 3-isoxazoyl which is substituted in the 5    position by —CH₃, 3 ethyl or propyl substituted by 4-morpholinyl    ethyl or propyl substituted by 4-morpholinyl which is substituted in    the 2 and 6 positions by —CH₃

methyl substituted by 2-morpholinyl which is substituted in the 4positon by —CH₂—C₆H₅

methyl substituted with 2-tetrahydrofuranyl, 2-dioxolane, ethyleneoxide, 2-furanyl, or 4-tetrahydropyranyl,

methyl substituted with 3-oxetanyl which is substituted in the 3position by —CH₃.

methyl substituted with 3-pyridinyl or 2-pyrazinyl.

methyl substituted with 3-pyridinyl which is substituted in the 6position by chlorine or methyl substituted with 2-pyridinyl which issubstituted in the 6 position by bromine,

ethyl substituted with 1-piperazinyl which is substituted in the 4position by 4-piperidinyl being substituted in the 1 position by—C(═O)—CH₃,

ethyl or propyl substituted with 1,2,3,6-tetrahydropyridine,

C₁₋₆alkyl substituted with azetidinyl,

propyl substituted by 1-azetidinyl which is substituted in the 3position by two fluorines, propyl substituted by 1-azetidinyl which issubstituted in the 3 position by one —OH,

ethyl or propyl substituted with 1-pyrrolidinyl or 2-pyrrolidinyl,

propyl substituted with 1-pyrrolidinyl which is substituted in the 3position by two fluorines or propyl substituted with 1-pyrrolidinylwhich is substituted in the 3 position by one fluorine,

propyl substituted with 1-pyrrolidinyl which is substituted in the 2position by —CH₂Cl,

ethyl or propyl substituted with 1-pyrrolidinyl which is substituted inthe 3 position by —OH,

ethyl or propyl substituted with 1-pyrrolidinyl which is substituted inthe 2 position by ═O,

propyl substituted with 1-pyrrolidinyl which is substituted in the 3position by —S(═O)₂—CH₃,

ethyl or propyl substituted with 1-pyrrolidinyl which is substituted inthe 3 position with —NH₂, ethyl substituted with 1-pyrrolidinyl which issubstituted in the 3 position with —N(CH₃)₂, propyl substituted with1-pyrrolidinyl which is substituted in the 3 position with —NHCH₃,

ethyl or propyl substituted with a) 1-pyrrolidinyl which is substitutedin the 2 position with —CH₃; b) 1-pyrrolidinyl which is substituted inthe 2 and the 5 position with —CH₃; or c) 1-pyrrolidinyl which issubstituted in the 2 position with two —CH₃,

ethyl substituted with 1-pyrrolidinyl which is substituted in the 2position with —C(═O)OH,

ethyl or propyl substituted with 1-pyrrolidinyl which is substituted inthe 2 position by —CH₂OH or with pyrrolidinyl which is substituted with—C(CH₃)₂OH or —CH₂CH₂OH,

propyl substituted with a) 1-pyrrolidinyl which is substituted in the 3position by 1-piperidinyl, or b) 1-pyrrolidinyl which is substituted inthe 3 position by 4-morpholinyl being substituted in positions 2 and 6by —CH₃,

ethyl or propyl substituted with 1-pyrrolidinyl which is substituted inthe 3 position by —CN, propyl substituted with 1-pyrrolidinyl which issubstituted in the 2 position by —CH₂CN,

propyl substituted with 1-pyrrolidinyl which is substituted in the 2position by —CH₂NH—S(═O)₂—CF₃,

methyl or ethyl substituted by a) 2-pyrrolidinyl which is substituted inthe 1 position by (CH₃)₃C—O—C(═O)— or b) 1-pyrrolidinyl which issubstituted in the 2 position by CH₃—O—C(═O)—,

methyl, ethyl or propyl substituted by 4-piperidinyl or 1-piperidinyl,

ethyl substituted by 1-piperidinyl which is substituted at the 4position by two fluorines,

methyl or ethyl substituted by a) 1-piperidinyl which is substituted atthe 4 position by one —OH or b) 4-piperidinyl which is substituted atthe 4 position by one —OH,

ethyl substituted by 1-piperidinyl which is substituted at the 3position or the 4 position by —NH₂,

ethyl substituted by 1-piperidinyl which is substituted at the 4position by —N(CH₃)₂,

methyl, ethyl or propyl substituted by a) 1-piperidinyl which issubstituted at the 2 position by —CH₃, b) 1-piperidinyl which issubstituted at the 2 and the 6 position by —CH₃, c) 4-piperidinyl whichis substituted at the 1 position by —CH(CH₃)₂, d) 4-piperidinyl which issubstituted at the 1 position by —CH₃, e) 1-piperidinyl which issubstituted at the 3 and the 5 position by —CH₃,

ethyl substituted by a) 1-piperidinyl which is substituted in the 4position by —C(CH₃)₂OH, b) 1-piperidinyl which is substituted in the 4position by —CH₂CH₂OH, c) 1-piperidinyl which is substituted in the 4position by —CH₂OH,

ethyl or propyl substituted with 1-piperidinyl which is substituted atthe 3 position with —CN,

methyl or ethyl substituted with a) 1-piperidinyl which is substitutedin the 4 position by CH₃CH₂—O—C(═O)—, or b) 4-piperidinyl which issubstituted in the 1 position by (CH₃)₃C—O—C(═O)—,

methyl substituted with 4-piperidinyl which is substituted in the 4position by —OH and in the 1 position by (CH₃)₃C—O—C(═O)—,

methyl substituted with 4-piperidinyl which is substituted in the 4position by —OCH₃ and in the 1 position by (CH₃)₃C—O—C(═O)—,

methyl or ethyl substituted with a) 1-piperidinyl which is substitutedin the 4 position by —OCH₃ or b) 4-piperidinyl which is substituted inthe 4 position by —OCH₃,

propyl substituted with 1-piperidinyl which is substituted in the 4position by —CF₃,

ethyl substituted withl-piperidinyl which is substituted in the 3position by —C(═O)—NH₂,

ethyl, propyl or butyl substituted with isoindole-1,3-dione,

ethyl substituted with 2-oxa-6-aza-spiro[3.3.]heptane,

ethyl substituted with 1,4-dioxa-8-aza-spiro[4.5]decane,

methyl substituted with 2-thiophenyl,

methyl substituted with 2-thiophenyl which is substituted at the 5position by chlorine, methyl substituted with 4-thiazolyl which issubstituted in the 2 position by —CH₃,

ethyl or propyl substituted with 1-piperazinyl,

ethyl substituted with 1-piperazinyl which is substituted in the 4position by CH₃—C(═O)—,

ethyl substituted with 1-piperazinyl which is substituted in the 4position by —CH₂CH₂OH,

ethyl or propyl substituted with a) 1-piperazinyl which is substitutedat the 3 and 5 positions by —CH₃ or b) 1-piperazinyl which issubstituted at the 4 position by —CH₃,

ethyl substituted with 1-piperazinyl which is substituted in the 3position by ═O,

ethyl substituted with 1-piperazinyl which is substituted in the 4position by —C(═O)—C₃H₅,

ethyl substituted with 5-tetrazolyl,

methyl substituted with a) 2-(1,3,4-oxadiazoyl) which is substituted atthe 5 position by —NH₂ or b) 2-(1,3,4-oxadiazoyl) which is substitutedat the 5 position by —NH—CH₂CH₂OH,

methyl, ethyl or propyl substituted with 1-pyrazoyl or 2-imidazoyl,

methyl, ethyl or propyl substituted with a) 1-imidazoyl which issubstituted at the 2 position by —CH₃, b) 3-pyrazolyl which issubstituted at the 1 and 5 positions by —CH₃, c) 1-imidazolyl which issubstituted at the 2 and 5 positions by —CH₃, d) 1-imidazolyl which issubstituted at the 2 and 4 positions by —CH₃, e) 2-imidazolyl which issubstituted at the 1 position by —CH₃ or f) 2-imidazolyl which issubstituted at the 1 position by —CH₂CH₃, methyl substituted with2-imidazolyl which is substituted in the 1 position by —S(═O)₂—N(CH₃)₂,

methyl substituted with 4-(1,2,3-triazolyl),

methyl substituted with a) 4-(1,2,3-triazolyl) which is substituted inthe 1 position by —CH₂CH₂OH or b) 4-(1,2,3-triazolyl) which issubstituted in the 2 position by —CH₂OH,

methyl substituted with 4-(1,2,3-triazolyl) which is substituted in the1 position by —CH₂C(═O)—OCH₂CH₃′

ethyl or propyl substituted with 3-oxazolidinyl which is substituted inthe 2 position by ═O,

propyl substituted with 4-thiomorpholinyl which is substituted in the 1position by two ═O groups,

ethyl substituted with 1-homopiperazinyl,

—CH₂—C₆H₅,

methyl substituted with phenyl which is substituted in the 2, 3 or 4position by chlorine,

-   C₁₋₆alkyl substituted with —NR¹⁰R¹¹, for example —CH₂CH₂NH₂,    —CH₂CH₂CH₂NH₂ or —CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂NHCH₃, —CH₂CH₂CH₂NHCH₃,    —CH₂CH₂NHCH₂CH₃, —CH₂CH₂NHCH(CH₃)₂ or —CH₂CH₂CH₂NHCH(CH₃)₂,    —CH₂CH₂N(CH₂CH₃)₂, —CH₂CH₂N(CH₂CH₃)(CH(CH₃)₂), —CH₂CH₂CH₂NHCH₂CF₃,    —CH₂CH₂NHCH₂CHF₂ or —CH₂CH₂NHCH₂CH₂F, —CH₂CH₂NH—C(═O)—CH₃,    —CH₂CH₂NH—S(═O)₂—CH₃, —CH₂CH₂CH₂NH—S(═O)₂—CH₃,    —CH₂CH₂NH—S(═O)₂—CH₂CH₃ or    —CH₂CH₂NH—S(═O)₂—CH(CH₃)₂—CH₂CH₂NH—S(═O)₂—N(CH₃)₂ or    —CH₂CH₂CH₂NH—S(═O)₂—N(CH₃)₂—CH₂CH₂NHCH₂CH₂OH,    —CH₂CH₂CH₂NH—C(═O)—C(OH)(CH₃)CF₃ or    —CH₂CH₂NH—C(═O)—C(OH)(CH₃)CF₃—CH₂CH₂NH—C(═O)—C₃H₅—CH₂CH₂NH—C(═O)-(piperidin-3-yl)    where the piperidinyl is substituted at the 1 position by —CH₃;    —CH₂CH₂NHCH₂CH₂CN—CH₂CH₂NHC₃H₅, —CH₂CH₂NHC₅H₉ or    —CH₂CH₂NH-(2,2,6,6-tetramethyl-piperidin-4-yl), —CH₂CH₂NHCH₂C₃H₅,    —CH₂CH₂NHCH₂-(tetrahydrofuran-2-yl), —CH₂CH₂NHC(═O)—CF₃ or    —CH₂CH₂CH₂NHC(═O)—CF₃, —CH₂CH₂NHCH₂Si(CH₃)₃, —CH₂CH₂N(CH₃)CH₂—C₆H₅,    —CH₂CH₂NH-(piperidin-4-yl) where the piperidinyl is substituted in    the 1 position by —S(═O)₂NH₂,-   C₁₋₆alkyl substituted with hydroxyl and —NR¹⁰R¹¹, for example    —CH₂CHOHCH₂NH₂, —CH₂CHOHCH₂NHCH₃ or —CH₂CHOHCH₂NHCH(CH₃)₂,    —CH₂CHOHCH₂NHCH₂CF₃,-   C₁₋₆alkyl substituted with one or two halogens and —NR¹⁰R¹¹, for    example —CH₂CHFCH₂NH₂,-   C₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl, for example    CH₂—C(═O)—O—CH₂CH₃ or —CH₂CH₂—C(═O)—O—CH₂CH₃,-   C₁₋₆alkyl substituted with —O—C(═OO)—NR¹⁰R¹¹, for example    —CH₂—C(═O)NH₂, —CH₂—C(═O)NHCH₃, —CH₂—C(═O)—NHCH₂CH₂OCH₃,    —CH₂—C(═O)—NH—CH₂CH₂-(pyrrolidin-1-yl) or —CH₂—C(═O)—NH—CH₂CH₂—    (imidazol-2-yl), —CH₂—C(═O)—NHCH₂CH₂OH, —CH₂—C(═O)—NHCH₂CH₂NH₂,-   C₁₋₆alkyl substituted with carboxyl, for example —CH₂C(═O)OH or    —CH₂CH₂C(═O)OH,-   C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹, for example    —CH₂CH₂—O—C(═O)—NHCH₃,-   C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, for example    —CH₂CH₂NH—S(═O)₂—CH₃, —CH₂CH₂CH₂NH—S(═O)₂—CH₃,    —CH₂CH₂NH—S(═O)₂—CH(CH₃)₂ or —CH₂CH₂NH—S(═O)₂—CH₂CH₃,-   C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—NR¹⁴R¹⁵, for example    —CH₂CH₂NH—S(═O)₂—N(CH₃)₂ or —CH₂CH₂CH₂NH—S(═O)₂—N(CH₃)₂,-   C₁₋₆alkyl substituted with hydroxyl and R⁹, for example-   propyl substituted with —OH and 1-pyrrolidinyl,-   propyl substituted with —OH and 1-pyrrolidinyl where the    1-pyrrolidinyl is substituted at the 3 position by two fluorines,-   propyl substituted with —OH and 1-pyrrolidinyl where the    1-pyrrolidinyl is substituted at the 3 position by a cyano group,-   propyl substituted with —OH and 4-morpholinyl,-   propyl substituted with —OH and 1-piperidinyl,-   propyl substituted with —OH and isoindole-1,3-dione,-   —C₁₋₆alkyl-C(R¹²)═N—O—R¹², for example —CH₂C(CH₃)═N—O—H,    —CH₂C(CH₂OCH₃)═N—O—H or —CH₂C(CH(CH₃)₂)═N—O—H-   C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, for example    -   —CH₂C(═O)NH₂,    -   —CH₂C(═O)NHCH₃,    -   —CH₂C(═O)—NHCH₂CH₂OCH₃,    -   —CH₂C(═O)—NH—CH₂CH₂— (pyrrolidin-1-yl) or —CH₂C(═O)—NH—CH₂CH₂—        (imidazol-2-yl), —CH₂C(═O)—NHCH₂CH₂OH, —CH₂C(═O)—NHCH₂CH₂NH₂,-   C₁₋₆alkyl substituted with —C(═O)—R⁹, for example —CH₂C(═O)—R⁹ and    R⁹ is 1-pyrrolidinyl,-   C₂₋₆alkynyl substituted with R⁹, for example —CH₂—C≡C—    (2-imidazolyl) wherein the 2-imidazolyl is substituted in the 1    position by —CH₃ or —CH₂—C≡C— (5-imidazol-yl) wherein the    5-imidazolyl is substituted in the 1 position by —CH₃,-   C₂₋₆alkenyl, for example —CH₂—CH═CH₂,-   C₂₋₆alkynyl, for example —CH₂—C≡C—H-   C₁₋₆alkyl substituted with C₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, for example    —CH₂—C(═O)—CH₂OCH₃, or-   R¹³.

In one embodiment the compound of formula (I) or formula (I⁰) is acompound of formula (I⁰′):

including any stereochemically isomeric form thereof;and a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof, wherein n, R² and R³ are as defined herein.

In one embodiment the compound of formula (I) or formula (I⁰) is acompound of formula (I⁰″),

including any stereochemically isomeric form thereof;and a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof, wherein R² and R³ are as defined herein.

In one embodiment the compound of formula (I) or formula (I⁰) is acompound of formula (I⁰′″)

including any stereochemically isomeric form thereof;and a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof, wherein R³ is as defined herein.

In one embodiment there is provided a compound of formula (I⁰′″) whereinR³ is as defined in any of the embodiments above, in particular asdefined at pages 86 line 20 to page 92 line 17.

In one embodiment the compound of formula (I) is a compound wherein oneR^(1a) is selected from hydrogen, C₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₁₋₄alkylsubstituted with amino or mono- or di(C₁₋₄alkyl)amino or—NH(C₃₋₈cycloalkyl), cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, and C₁₋₄alkylsubstituted with one or more fluoro atoms; and the other R^(1a) isselected from C₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₁₋₄alkyl substituted withamino or mono- or di(C₁₋₄alkyl)amino or —NH(C₃₋₈cycloalkyl),cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, and C₁₋₄alkyl substituted with oneor more fluoro atoms; and wherein n, R¹, R² and R³ are as definedherein.

In one embodiment the compound of formula (I) is a compound wherein eachR^(1a) is independently selected from C₁₋₄alkyl, hydroxyC₁₋₄alkyl,C₁₋₄alkyl substituted with amino or mono- or di(C₁₋₄alkyl)amino or—NH(C₃₋₈cycloalkyl), cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, and C₁₋₄alkylsubstituted with one or more fluoro atoms; and the other R^(1a) isselected from C₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₁₋₄alkyl substituted withamino or mono- or di(C₁₋₄alkyl)amino or —NH(C₃₋₈cycloalkyl),cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, and C₁₋₄alkyl substituted with oneor more fluoro atoms; and wherein n, R¹, R² and R³ are as definedherein.

In one embodiment the compound of formula (I) is a compound wherein eachR^(1a) is hydrogen; and wherein n, R¹, R² and R³ are as defined herein.

In one embodiment every alkyl group within the R³ definition is aC₁₋₄alkyl group.

In one embodiment every alkyl group within the R³ definition is a linearC₁₋₆alkyl group, in particular a linear C₁₋₄alkyl group.

In one embodiment the compound of formula (I) is a compound of formula(I′):

including any stereochemically isomeric form thereof;and a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof, wherein n, R^(1a), R² and R³ are as defined herein.

In one embodiment the compound of formula (I) is a compound of formula(I″)

including any stereochemically isomeric form thereof;and a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof, wherein R^(1a), R² and R³ are as defined herein.

In one embodiment the compound of formula (I) is a compound of formula(I′″)

including any stereochemically isomeric form thereof;and a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof, wherein R^(1a) and R³ is as defined herein.

In one embodiment there is provided a compound of formula (I), (I′),(I″), (I′″), (I⁰), (I⁰′), (I⁰″) or (I⁰′″) wherein every alkyl groupwithin the R³ definition is a linear C₁₋₆alkyl group. In one embodimentthere is provided a compound of formula (I), (I′), (I″), (I′″), (I⁰),(I⁰′), (I⁰″) or (I⁰′″) wherein every alkyl group within the R³definition is a C₁₋₄alkyl group. In one embodiment there is provided acompound of formula (I), (I′), (I″), (I′″), (I⁰), (I⁰′), (I⁰″) or (I⁰′″)wherein every alkyl group within the R³ definition is a linear C₁₋₄alkylgroup.

For the avoidance of doubt, it is to be understood that each general andspecific preference, embodiment and example for one substituent may becombined with each general and specific preference, embodiment andexample for one or more, preferably, all other substituents as definedherein and that all such embodiments are embraced by this application.

Methods for the Preparation of Compounds of Formula (I)

In this section, as in all other sections of this application unless thecontext indicates otherwise, references to formula (I) also include allother sub-groups and examples thereof as defined herein.

In general, compounds of formula (I) can be prepared according to thefollowing reaction Scheme 1.

In scheme 1, an intermediate of formula (IV) is prepared by reacting anintermediate of formula (II) wherein W₁ and W₂, each independentlyrepresent a suitable leaving group, such as for example halo, e.g.chloro or bromo and the like, with an intermediate of formula (III) inthe presence of a suitable catalyst, such as for exampletetrakis(triphenylphosphine)palladium (0) or palladium (II) acetate, asuitable base, such as for example sodium carbonate, a suitable ligand,such as for example triphenylphosphine, and a suitable solvent orsolvent mixture, such as for example ethylene glycol dimethylether andwater. An intermediate of formula (II) wherein W₁ is chloro and W₂ isbromo can be prepared by reacting 7-bromo-2(1H)-quinoxalinone withphosphorus oxychloride, or alternatively with thionyl chloride andN,N-dimethylformamide in a suitable solvent, such as, for exampletoluene. An intermediate of formula (IV) can also be prepared byreacting 7-bromo-2-(1H-pyrazol-4-yl)quinoxaline with an intermediateW₁₀—R¹ wherein W₁₀ represents a suitable leaving group, such as forexample halo, e.g. bromo and the like. An intermediate of formula (IV)wherein the R¹ substituent carries a suitable protective group can beprepared according to the same protocol but wherein7-bromo-2-(1H-pyrazol-4-yl)quinoxaline is reacted with an intermediateW₁₀—R¹—P wherein P represents a suitable protective group, such as forexample —C(═O)—O—C(CH₃)₃. The intermediate of formula (IV) is thenfurther reacted in a next step with an intermediate of formula (V) inthe presence of a suitable catalyst, such as for example palladium (II)acetate, a suitable base, such as sodium tert-butoxide or Cs₂CO₃, asuitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], and asuitable solvent or solvent mixture, such as for example dioxane orethylene glycol dimethylether and water, resulting in an intermediate offormula (VI). Said intermediate of formula (VI) can then be reacted withan intermediate of formula (VII) wherein W₃ represents a suitableleaving group, such as for example halo, e.g. bromo and wherein R^(x)and R^(y) represent C₁₋₄alkyl, and R^(z) represent C₁₋₄alkyl or phenyl,for instance R^(x) and R^(y) represent CH₃ and R^(z) represents C(CH₃)₃or phenyl, in the presence of a suitable base, such as for examplesodium hydride, and a suitable solvent, such as for exampleN,N-dimethylformamide or N,N-dimethylacetamide, resulting in anintermediate of formula (VIII). Intermediates of formula (VIII) orintermediates of formula (VIII) wherein the R¹ substituent carries asuitable protective group can also be prepared by reacting anintermediate of formula (IV) or an intermediate of formula (IV) whereinthe R¹ substituent carries a suitable protective group with anintermediate of formula (XXIII′) wherein R^(3a′) represent—C₁₋₆alkyl-O—Si(R^(x))(R^(y))(R^(z)) in the presence of a suitablecatalyst, such as for example palladium (II) acetate, a suitable ligand,such as for example racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl,a suitable base, such as for example Cs₂CO₃, and a suitable solvent,such as for example 1,2-dimethoxyethane. Intermediates of formula (VIII)can be converted into a compound of formula (I) wherein R³ represents—C₁₋₆alkyl-OH, said compounds being represented by formula (I-a) orcompounds of formula (I-a) wherein the R¹ substituent carries a suitableprotective group, by reaction with tetrabutylammonium fluoride in thepresence of a suitable solvent, such as for example tetrahydrofuran.This type of reaction can also be performed in the presence of asuitable acid, such as for example acetic acid or HCl, and a suitablesolvent, such as for example tetrahydrofurane or dioxane. Alternatively,an intermediate of formula (VI) can react with an intermediate offormula (VII′) wherein W₃ represents a suitable leaving group, such asfor example halo, e.g. bromo and the like, in the presence of a suitablebase, such as for example sodium hydride, and a suitable solvent, suchas for example N,N-dimethylformamide or N,N-dimethylacetamide, resultingin an intermediate of formula (XXV) which can then be deprotected in thepresence of a suitable acid, such as for example HCl, and a suitablesolvent, such as for example an alcohol, e.g. methanol or isopropanol,to give a compound of formula (I-a). The compounds of formula (I-a) orcompounds of formula (I-a) wherein the R¹ substituent carries a suitableprotective group can be reacted with methanesulfonyl chloride in thepresence of a suitable base, such as for example triethylamine,diisopropylethanamine or N,N-dimethyl-4-aminopyridine, and a suitablesolvent, such as for example dichloromethane or tetrahydrofuran, toresult in an intermediate of formula (IX) (mesylate derivative) or anintermediate of formula (IX′) (chloride derivative) or intermediates offormula (IX) or (IX′) wherein the R¹ substituent carries a suitableprotective group. Intermediates of formula (IX) or (IX′) can then bereacted with an intermediate of formula (X) to obtain a compound offormula (I) wherein R³ represents C₁₋₆alkyl substituted with NR¹⁰R¹¹,said compounds being represented by formula (I-b) or compounds offormula (I-b) wherein the R¹ substituent carries a suitable protectivegroup. This reaction may optionally be performed in the presence of asuitable base, such as for example triethylamine, K₂CO₃, Na₂CO₃ orsodium hydride and optionally a suitable solvent, such as for exampleacetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide,1-methyl-pyrrolidinone, a suitable alcohol, e.g. 1-butanol and the like.This type of reaction can also be performed with a suitable salt of theintermediate of formula (X), e.g. HCl salt of intermediate of formula(X), or may be performed in the presence of potassium iodide. In thisway compounds wherein R³ represents iodoC₁₋₆alkyl can be obtained.Compounds of formula (I-b) wherein the R¹ substituent carries a suitableprotective group can be converted in a compound of formula (I-b) byreaction with a suitable acid, such as for example trifluoroacetic acid,in the presence of a suitable solvent, such as for exampledichloromethane.

Intermediates of formula (IX) can also react with a suitable nitrogencontaining ring within the definition of R⁹, said ring being representedby formula (XXI) or a suitable salt of an intermediate of formula (XXI),in the presence of a suitable solvent, such as for example acetonitrile,1-methyl-2-pyrrolidinone, or an alcohol, e.g. 1-butanol, optionally inthe presence of potassium iodide or a suitable base, such as for exampleNa₂CO₃, K₂CO₃ or triethylamine, resulting in a compound of formula(I-d). Intermediates of formula (IX) can also react with an intermediateof formula (X-a) wherein P represents a suitable protective group, suchas for example —C(═O)—O—C(CH₃)₃, in the presence of a suitable base,such as for example sodium hydride, and a suitable solvent, such as forexample dimethylacetamide, resulting in an intermediate of formula (XXX)which can be deprotected to a compound of formula (I-b-1) in thepresence of a suitable acid, such as for example HCl or trifluoroaceticacid, and a suitable solvent, such as for example dichloromethane or analcohol, e.g. methanol. Intermediates of formula (XXX) can also beprepared by reacting an intermediate of formula (VI) with anintermediate of formula W₆—C₁₋₆alkyl-NR¹⁰P wherein W₆ represents asuitable leaving group, such as for example halo, e.g. bromo and thelike, or —O—S(═O)₂—CH₃, and P is as defined above, in the presence of asuitable base, such as for example sodium hydride, and a suitablesolvent, e.g. N,N-dimethylformamide or N,N-dimethylacetamide.Alternatively compounds of formula (I-d) or (1-b-1) can also be preparedby reacting respectively an intermediate of formula (VI) with anintermediate of formula W₆—C₁₋₆alkyl-Ncycle or W₆—C₁₋₆alkyl-NHR¹⁰wherein W₆ is as defined above.

Intermediates of formula (VI) can react with W₆—R^(3a) wherein W₆represents a suitable leaving group, such as for example halo, e.g.bromo and the like, or —O—S(═O)₂—CH₃, and R^(3a) represents optionallysubstituted C₁₋₆alkyl, such as for example —CH₂—C₃H₅, in the presence ofa suitable base, such as for example sodium hydride or Cs₂CO₃, and asuitable solvent, such as for example N,N-dimethylformamide,N,N-dimethylacetamide or acetonitrile, resulting in a compound offormula (I-c). In this way, compounds of formula (I-c) wherein R³represents —S(═O)₂—N(CH₃)₂ can also be prepared by reacting anintermediate of formula (VI) with dimethylsulfamoyl chloride, in thepresence of a suitable base, such as for example NaH, and a suitablesolvent, such as for example N,N-dimethylformamide.

Compounds of formula (I-c) wherein R^(3a) represents —CH₂—C(OH)(R′)(R″)wherein R′ represents optionally substituted C₁₋₄alkyl and R″ representshydrogen or optionally substituted C₁₋₄alkyl, said compounds beingrepresented by formula (I-c-1), can be prepared by reacting theintermediate of formula (VI) with an intermediate of formula (XXII) inthe presence of a suitable base, such as for example sodium hydride,Cs₂CO₃, or potassium hydroxide, and a suitable solvent, such as forexample N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile orwater.

Intermediates of formula (IV) can also react with an intermediate offormula (XXIII) in the presence of a suitable catalyst, such as forexample palladium (II) acetate or tris(dibenzylideneacetone)dipalladium(0), a suitable base, such as for example sodium tert-butoxide, asuitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine] or2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, and a suitablesolvent, such as for example dioxane, resulting in a compound of formula(I-c).

Compounds of formula (I-b) wherein R¹¹ is C₁₋₆alkyl substituted withamino, said compounds being represented by formula (I-b-2), can also beprepared according to the following reaction Scheme 1A.

In Scheme 1A, a compound of formula (I-b-1) is reacted withN-(3-bromopropyl)phtalimide in the presence of a suitable base, such asfor example potassium carbonate, and a suitable solvent, such as forexample acetonitrile, resulting in an intermediate of formula (XXXVI)which can be converted into a compound of formula (I-b-2) by reactionwith hydrazine in the presence of a suitable solvent, such as forexample an alcohol, e.g. ethanol.

Compounds of formula (I-b) wherein R¹ is hydrogen, said compounds beingrepresented by formula (I-b-3) can be prepared according to reactionScheme 1A1.

In Scheme 1A1, an intermediate of formula (I-a-1) is reacted withmethanesulfonyl chloride in the presence of a suitable base, such as forexample triethylamine, and a suitable solvent, such as for exampledichloromethane resulting in an intermediate of formula (IX-1) whereinR^(u) represents —O—S(═O)₂—CH₃, which is converted into a compound offormula (I-b-3) by reaction with an intermediate of formula (X) in thepresence of a suitable solvent, such as for example acetonitrile.

It is considered to be within the knowledge of the person skilled in theart to recognize in which condition and for which definitions of R^(1a)in the reactions of Scheme 1a and Scheme 1 al a protective group may beappropriate for the reactions to be carried out.

For instance, a hydroxyl group within the definition of R^(1a) may beprotected with a tert. butyldimethylsilyl moiety; a NH group within thedefinition of R^(1a) may be protected with a —C(═O)—O—C(CH₃)₃ group.

It is also considered to be within the knowledge of the person skilledin the art to recognize appropriate deprotection reactions.

Compounds of formula (I) wherein R³ represents optionally substitutedC₂₋₆alkynyl, said compounds being represented by formula (I-k), can beprepared according to reaction Scheme 1B.

In Scheme 1B, an intermediate of formula (VI) is reacted with anintermediate of formula W₁₁—R^(3b) wherein R^(3b) represents optionallysubstituted C₂₋₆alkynyl and W₁₁ represents a suitable leaving group suchas for example halo, e.g. chloro, or —O—S(═O)₂—CH₃, in the presence of asuitable base, such as for example NaH, and a suitable solvent, such asfor example N,N-dimethylformamide. The intermediate W₁₁—R^(3b) whereinW₁₁ represents —O—S(═O)₂—CH₃, can be prepared by reacting thecorresponding alcohol derivative with methanesulfonyl chloride in thepresence of a suitable base, such as for example triethylamine or4-dimethylaminopyridine, and a suitable solvent, such as for exampledichloromethane.

Compounds of formula (I-k), wherein R^(3b) represents C₂₋₆alkynylsubstituted with hydroxyl, said compounds being represented by formula(I-k-1), can be prepared according to the following reaction Scheme 1C.

In Scheme 1C, an intermediate of formula (VI) is reacted with anintermediate of formula (XXXVIII) in the presence of a suitable base,such as for example NaH, and a suitable solvent, such as for exampleN,n-dimethylformamide, resulting in an intermediate of formula (VIII′),which is converted into a compound of formula (I-k-1) by reaction with asuitable acid, such as for example trifluoroacetic acid, in the presenceof a suitable solvent, such as for example tetrahydrofuran.

Compounds of formula (I-k), wherein R^(3b) represents C₂₋₆alkynyl, saidcompounds being represented by formula (I-k-2), can be preparedaccording to the following reaction Scheme 1D.

In Scheme 1D, a compound of formula (I-k-2) is prepared by deprotectingan intermediate of formula (XXXXII) in the presence of a suitable base,such as for example K₂CO₃, and a suitable solvent, such as for examplean alcohol, e.g. methanol and the like. Said intermediate of formula(XXXXII) can be prepared by reacting an intermediate of formula (VI)with W₁₃—C₂₋₆alkynyl-Si(CH₃)₃ in the presence of a suitable base, suchas for example NaH, and a suitable solvent, such as for exampleN,N-dimethylformamide.

Compounds of formula (I), wherein R³ represents ethyl substituted with—P(═O)(OC₁₋₆alkyl)₂, said compounds being represented by formula (I-I),can be prepared according to the following reaction Scheme 1E.

In scheme 1E, an intermediate of formula (VI) is reacted withdi(C₁₋₆alkyl)vinylphosphonate in the presence of a suitable catalyst,such as for example tri-N-butylphosphine, and a suitable solvent, suchas for example acetonitrile resulting in a compound of formula (I-I).

Intermediates of formula (VI) can also be prepared according to thefollowing reaction Scheme 2.

In Scheme 2, an intermediate of formula (XII) is prepared by reacting anintermediate of formula (X1) wherein W₁ represents a suitable leavinggroup, such as for example halo, e.g. chloro and the like, with anintermediate of formula (III) in the presence of a suitable catalyst,such as for example tetrakis(triphenylphosphine)palladium (0), asuitable base, such as for example Na₂CO₃, and a suitable solvent orsolvent mixture, such as for example ethylene glycol dimethylether andwater. The intermediate of formula (XII) is hydrogenated in a next stepto an intermediate of formula (XIII) in the presence of a suitablecatalyst, such as for example Nickel, and a suitable solvent, such asfor example an alcohol, e.g. methanol, or tetrahydrofuran, or mixturesthereof.

Intermediates of formula (XIII) can also be prepared by reacting anintermediate of formula (IV) with NH₄OH in the presence of Cu₂O. In anext step, the intermediate of formula (XIII) is reacted with anintermediate of formula (XIV) wherein W₅ represents a suitable leavinggroup, such as for example halo, e.g. bromo and the like, in thepresence of a suitable catalyst, such as for example palladium (II)acetate, a suitable base, such as for example sodium tert-butoxide, asuitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], and asuitable solvent, such as for example ethylene glycol dimethyl ether ordioxane, resulting in an intermediate of formula (VI). This reaction mayalso be performed in the presence of Pd₂(dba)₃ as catalyst, Xphos asligand, a suitable base, such as for example Cs₂CO₃, and a suitablesolvent, such as for example an alcohol, e.g. butanol.

Intermediates of formula (IV) wherein R¹ is hydrogen can be convertedinto an intermediate of formula (IV) wherein R¹ is other than hydrogen,said R¹ being represented by R^(1′), by reaction with W₁₄—R^(1′) whereinW₁₄ is a suitable leaving group, such as for example halo, e.g. bromo,in the presence of a suitable base, such as for example NaH, and asuitable solvent, such as for example N,N-dimethylformamide.

Intermediates of formula (VI) can alternatively also be preparedaccording to the following reaction Scheme 3.

In Scheme 3, an intermediate of formula (XV) is reacted with anintermediate of formula (V) in the presence of a suitable catalyst, suchas for example palladium (II) acetate, a suitable base, such as forexample sodium tert-butoxide, a suitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], and asuitable solvent, such as for example ethylene glycol dimethyl ether,resulting in an intermediate of formula (XVI). In a next step, theintermediate of formula (XVI) is reacted with P(═O)Cl₃ orchlorosuccinimide, optionally in the presence of a solvent, such as forexample acetonitrile, resulting in an intermediate of formula (XVII)which is converted into an intermediate of formula (VI) by reaction withan intermediate of formula (III) in the presence of a suitable catalyst,such as for example tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0), a suitable base, such as forexample Na₂CO₃ or K₃PO₄, optionally in the presence of a suitableligand, such as for example2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, and a suitable solvent,such as for example ethylene glycol dimethylether.

In the above reaction, an intermediate of formula (III) can react in itsprotected form, such as for example

The resulting protected intermediate of formula (VI) can be convertedinto the deprotected —C₁₋₆alkyl-OH intermediate by reaction withtetrabutylammonium fluoride, in the presence of a suitable solvent, suchas for example tetrahydrofuran. Said —C₁₋₆alkyl-OH can be converted into—C₁₋₆alkyl-NH₂ by first reacting the —C₁₋₆alkyl-OH with methanesulfonylchloride in the presence of a suitable base, such as for exampletriethylamine, and a suitable solvent, such as for exampledichloromethane, followed by reacting the obtained intermediate withdi-tert-butyl-iminocarboxylate in the presence of a suitable base, suchas for example NaH, and a suitable solvent, such as for exampleN,N-dimethylformamide, followed by reaction with a suitable acid, suchas for example trifluoroacetic acid, in a suitable solvent, such as forexample dichloromethane.

Intermediates of formula (VIII) can alternatively also be preparedaccording to the following reaction Scheme 4.

In Scheme 4, an intermediate of formula (XVII) is reacted with anintermediate of formula (VII) in the presence of a suitable base, suchas for example sodium hydride, and a suitable solvent, such as forexample N,N-dimethylformamide, resulting in an intermediate of formula(XVIII). The intermediate of formula (XVIII) can then be reacted with anintermediate of formula (III) in the presence of a suitable catalyst,such as for example Pd₂(dba)₃, a suitable base, such as for exampleK₃PO₄, a suitable ligand, such as for example2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl or S-Phos, and asuitable solvent, such as for example dioxane or water or mixturesthereof.

Intermediates of formula (VIII′) can be prepared according to thefollowing reaction Scheme 4A.

In Scheme 4A, an intermediate of formula (XVIII) is reacted with anintermediate of formula (XXXVII) in the presence of a suitable catalyst,such as for example tetrakis(triphenylphisphine)palladium (0), and asuitable solvent, such as for example toluene.

Intermediates of formula (VIII′) can be further reacted according to thefollowing reaction Scheme 4B.

In Scheme 4B, intermediates of formula (VIII′) wherein R¹ representshydrogen, said intermediates being represented by formula (VIII′-a), canbe converted into an intermediate of formula (VIII′) wherein R¹represents haloC₁₋₆alkyl, said intermediates being represented byformula (VIII′-b) by reaction with W₁₂—C₁₋₆alkyl-halo wherein W₁₂represents a suitable leaving group, such as for example halo, e.g.chloro, in the presence of a suitable base, such as for example NaH, anda suitable solvent, such as for example N,N-dimethylformamide. Saidintermediates of formula (VIII′-b) can be converted into an intermediateof formula (VIII′-c) wherein R¹ represents an optionally substituted R⁶,by reaction with optionally substituted R⁶ in the presence of a suitablebase, such as for example K₂CO₃, and a suitable solvent, such as forexample acetonitrile. When in an intermediate of formula (VIII′-c) theR⁶ carries a hydroxyl group as in an intermediate of formula(VIII′-c-1), then said hydroxyl group can be protected by a suitableprotective group P, such as for example —O—C(═O)—C₁₋₆alkyl, by reactionwith C₁₋₆alkyl-C(═O)—W₁₂, in the presence of a suitable base, such asfor example triethylamine, 4-dimethylaminopyridine, and a suitablesolvent, such as for example dichloromethane, resulting in anintermediate of formula (VIII′-c-2) which can be converted into anintermediate of formula (XXXIX) by reaction with tetrabutylammoniumfluoride in the presence of a suitable solvent, such as for exampletetrahydrofuran. Said intermediate of formula (XXXIX) can be convertedinto an intermediate of formula (XXXX) by reaction with methansulfonylchloride in the presence of a suitable base, such as for exampletriethylamine, and a suitable solvent, such as for exampledichloromethane, which can be converted into an intermediate of formula(XXXXI) by reaction with an intermediate of formula (X) in a suitablesolvent, such as for example acetonitrile. Said intermediate of formula(XXXXI) can then be deprotected into a compound of formula (I-b-4) inthe presence of a suitable base, such as for example K₂CO₃, and asuitable solvent, such as for example an alcohol, e.g. methanol and thelike.

Intermediates of formula (VIII′) can also be reacted to preparecompounds of the present invention according to the reaction schemes aspresented in Scheme 1. It is considered to be within the knowledge ofthe person skilled in the art to recognize in which condition and forwhich definitions of R^(1a) a protective group may be appropriate forthe reactions to be carried out. For instance, a hydroxyl group withinthe definition of R^(1a) may be protected with a tert.butyldimethylsilyl moiety; a NH group within the definition of R^(1a)may be protected with a —C(═O)—O—C(CH₃)₃ group.

It is also considered to be within the knowledge of the person skilledin the art to recognize appropriate deprotection reactions.

Compounds of formula (I) wherein R³ represents optionally substitutedC₁₋₆alkyl, said compounds being represented by formula (I-c), can alsobe prepared according to the below reaction Scheme 5.

In Scheme 5, an intermediate of formula (XVll) is reacted with W₆—R^(3a)wherein W₆ represents a suitable leaving group, such as for examplehalo, e.g. bromo and the like, and R^(3a) represents optionallysubstituted C₁₋₆alkyl, such as for example —CH₂—C₃H₅, in the presence ofa suitable base, such as for example sodium hydride, and a suitablesolvent, such as for example N,N-dimethylformamide, resulting in anintermediate of formula (XIX). In a next step, the intermediate offormula (XIX) is reacted with an intermediate of formula (III) in thepresence of a suitable catalyst, such as for exampletetrakis(triphenyl)phosphine palladium or Pd₂(dba)₃(tris(dibenzylideneacetone) dipalladium (0)), a suitable ligand, such as2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, a suitable base, suchas for example Na₂CO₃ or K₃PO₄, and a suitable solvent, such as forexample ethylene glycol dimethylether or dioxane or water.

Compounds of formula (I-c) can alternatively also be prepared accordingto the below reaction Scheme 6.

In Scheme 6, an intermediate of formula (IV) is reacted with R^(3a)—NH₂in the presence of a suitable catalyst, such as for example palladium(II) acetate, a suitable base, such as for example sodium tert-butoxide,and a suitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], resultingin an intermediate of formula (XX) which is reacted in a next step withan intermediate of formula (XIV) in the presence of a suitable catalyst,such as for example palladium (II) acetate or Pd₂(dba)₃(tris(dibenzylidene acetone) dipalladium (0)), a suitable ligand such asfor example 2-dicyclohexylphosphino-tris-isopropyl-biphenyl or1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], asuitable base, such as for example sodium tert-butoxide, and a suitablesolvent, such as for example ethylene glycol dimethylether.

Compounds of formula (I) wherein R³ is C₁₋₆alkyl substituted with5-amino-1,3,4-oxadiazolyl can be prepared according to the belowreaction Scheme 7.

In Scheme 7, a compound of formula (I-h) is reacted with NH₂—NH₂ in thepresence of a suitable solvent, such as for example an alcohol, e.g.ethanol resulting in an intermediate of formula (XXXI) which is thenreacted in a next step with W₈—CN, wherein W₈ represents a suitableleaving group, such as for example halo, e.g. bromo, in the presence ofa suitable base, such as for example NaHCO₃, and a suitable solvent,such as for example water or dioxane.

Compounds of formula (I) wherein R³ is C₁₋₆alkyl substituted with3,3-dimethyl-morpholine can be prepared according to the below reactionScheme 7.A

In Scheme 7A, a compound of formula (I-j″) is reacted with2-amino-2-methyl-1-propanol in the presence of a suitable base, such asfor example NaH and in the presence of a suitable solvent, such as forexample N,N-dimethylformamide resulting in an intermediate of formula(XXXII) of which the NH₂ moiety is protected by a suitable protectinggroup P, such as for example —C(═O)—O—C(CH₃)₃, by reaction with forinstance di-tert-butyl dicarbonate in the presence of a suitablesolvent, such as for example dioxane, and a suitable base, such as forexample NaHCO₃, resulting in an intermediate of formula (XXXIII). In anext step, said intermediate is reacted with methanesulfonyl chloride inthe presence of a suitable solvent, such as for example dichloromethane,and a suitable base, such as for example triethylamine resulting in anintermediate of formula (XXXIV) which is converted into an intermediateof formula (XXXV) by reaction with a suitable acid, such as for exampletrifluoroacetic acid, in the presence of a suitable solvent, such as forexample dichloromethane. The intermediate of formula (XXXV) is convertedinto a compound of formula (I-j′) by reaction with a suitable base, suchas for example N,N-diisopropylethylamine and triethylamine in thepresence of a suitable solvent, such as for example an alcohol, e.g.methanol.

As already shown above, compounds of formula (I) or some of theabove-described intermediates can be prepared by deprotecting thecorresponding protected compounds. Other protection-deprotectionreactions are shown in the following reaction Scheme 8.

In Scheme 8, compounds of formula (I) wherein R¹ representshydroxyC₆alkyl, said compounds being represented by formula (I-e), canbe prepared by deprotecting an intermediate of formula (XXVI) in thepresence of a suitable acid, such as for example HCl or trifluoroaceticacid, or a suitable de-silylating agent, such as for example tetrabutylammonium fluoride, and a suitable solvent, such as an alcohol, e.g.methanol, or tetrahydrofuran. Intermediates of formula (XXVI) can beprepared by reacting a compound of formula (I) wherein R¹ s hydrogen,said compounds being represented by formula (I-f), with an intermediateof formula (XXIV) wherein W9 represents a suitable leaving group, suchas for example halo, e.g. bromo and the like, and P represents asuitable protective group, such as for example —O—Si(CH₃)₂(C(CH₃)₃) or

in the presence of a suitable base, such as for example sodium hydrideor K₂CO₃, and a suitable solvent, such as for exampleN,N-dimethylformamide or acetonitrile. Compounds of formula (I) whereinR¹ represents C₁₋₆alkyl substituted with —C(═O)—R⁶ wherein R⁶ is anappropriate nitrogen containing ring linked to the C(═O) moiety via thenitrogen atom, said compounds being represented by formula (I-g), can beprepared by reacting an intermediate of formula (XXIX) with anintermediate of formula (XXI) in the presence of suitable peptidecoupling reagents such as, 1-hydroxy-benzotriazole and1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl. Intermediates offormula (XXIX) can be prepared by reacting an intermediate of formula(XXVIII) with LiOH in the presence of a suitable solvent, such as forexample tetrahydrofuran or water. Intermediates of formula (XXVIII) canbe prepared by reacting a compound of formula (I-f) with an intermediateof formula (XXVII) wherein W₉ is as defined above, in the presence of asuitable base, such as for example sodium hydride, and a suitablesolvent, such as for example N,N-dimethylformamide.

Compounds of formula (I-i) can be prepared starting from an intermediateof formula (XXIX) by reaction with NHR⁴R⁵ in the presence of suitablepeptide coupling reagents such as 1-hydroxy-benzotriazole and1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl and a suitable base,such as triethylamine, and a suitable solvent, such as for exampledichloromethane.

Further protection-deprotection reactions can also be used as outlinedin the following reaction Scheme 9.

In Scheme 9, the following reaction conditions apply:

A; in the presence of a suitable base, such as for example sodiumhydride, and a suitable solvent, such as for exampleN,N-dimethylformamide.B: in the presence of a suitable catalyst, such as for example palladium(II)acetate, a suitable base, such as for example sodium tert-butoxide,a suitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], and asuitable solvent, such as for example dioxane or ethylene glycoldimethylether.C: in the presence of a suitable catalyst, such as for example palladium(II)acetate, a suitable base, such as for example sodium tert-butoxide,a suitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], and asuitable solvent, such as for example dioxane or ethylene glycoldimethylether.D: in the presence of a suitable base, such as for exampletriethylamine, and a suitable solvent, such as for exampledichloromethane.E: in the presence of a suitable base, such as for example K₂CO₃, and asuitable solvent, such as for example 1-methyl-2-pyrrolidinone.F: in the presence of hydrazine monohydrate, and a suitable solvent,such as for example an alcohol, e.g. ethanol.G: in the presence of a suitable base, such as for example K₂CO₃, and asuitable solvent, such as for example tetrahydrofuran.

It is considered to be within the knowledge of the person skilled in theart to recognize in which condition and on which part of the molecule aprotective group may be appropriate. For instance, protective group onthe R¹ substituent or on the pyrrazole moiety, or protective group onthe R³ substituent or on the R² substituent or combinations thereof. Theskilled person is also considered to be able to recognize the mostfeasible protective group, such as for example —C(═O)—O—C₁₋₄alkyl or

or O—Si(CH₃)₂(C(CH₃)₃) or —CH₂—O—CH₂CH₂—O—CH₃.

The present invention also comprises deuterated compounds. Thesedeuterated compounds may be prepared by using the appropriate deuteratedintermediates during the synthesis process. For instance an intermediateof formula (IV-a)

can be converted into an intermediate of formula (IV-b)

by reaction with iodomethane-D3 in the presence of a suitable base, suchas for example cesium carbonate, and a suitable solvent, such as forexample acetonitrile.

The compounds of formula (I) may also be converted into each other viaart-known reactions or functional group transformations.

For instance, compounds of formula (I) wherein R¹ representstetrahydropyranyl can be converted into a compound of formula (I)wherein R¹ represents hydrogen, by reaction with a suitable acid, suchas for example HCl or trifluoroacetic acid, in the presence of asuitable solvent, such as for example dichloromethane, dioxane, or analcohol, e.g. methanol, isopropanol and the like.

Compounds of formula (I) wherein R¹ or R³ represent monohaloalkyl, canbe converted into a compound of formula (I) wherein R¹ or R³ representC₁₋₆alkyl substituted with a ring moiety as defined hereinabove by theintermediate of formula (XXI) and linked to the C₁₋₆alkyl moiety by thenitrogen atom, by reaction with an intermediate of formula (XXI)optionally in the presence of a suitable base, such as for exampletriethylamine or K₂CO₃ or sodium hydride, and optionally in the presenceof a suitable solvent, such as for example acetonitrile,N,N-dimethylformamide or 1-methyl-2-pyrrolidinone.

Compounds of formula (I) wherein R¹ or R³ represents C₁₋₆alkyl-OH, canbe converted into a compound of formula (I) wherein R¹ or R³ representC₁₋₆alkyl-F by reaction with diethylaminosulfur trifluoride in thepresence of a suitable solvent, such as for example dichloromethane andin the presence of catalytic amounts of an alcohol, such as for exampleethanol. Likewise, a compound of formula (I) wherein R¹ or R³ representC₁₋₆alkyl substituted with R⁶ or R⁹ wherein said R⁶ or R⁹ is substitutedwith OH, can be converted into a compound of formula (I) wherein R¹ orR³ represent C₁₋₆alkyl substituted with R⁶ or R⁹ wherein said R⁶ or R⁹is substituted with F, by reaction with diethylaminosulfur trifluoridein the presence of a suitable solvent, such as for exampledichloromethane.

Compounds of formula (I) wherein R¹ or R³ represent C₁₋₆alkylsubstituted with R⁶ or R⁹ wherein said R⁶ or R⁹ is substituted with—C(═O)—O—C₁₋₆alkyl, can be converted into a compound of formula (I)wherein R¹ or R³ represent C₁₋₆alkyl substituted with R⁶ or R⁹ whereinsaid R⁶ or R⁹ is substituted with —CH₂—OH, by reaction with LiAlH₄ inthe presence of a suitable solvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith 1,3-dioxo-2H-isoindol-2-yl, can be converted into a compound offormula (I) wherein R³ represents C₁₋₆alkyl substituted with amino, byreaction with hydrazine monohydrate in the presence of a suitablesolvent, such as for example an alcohol, e.g. ethanol.

Compounds of formula (I) wherein R¹ or R³ represent C₁₋₆alkylsubstituted with amino, can be converted into a compound of formula (I)wherein R¹ or R³ represents C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, by reaction with Cl—S(═O)₂—C₁₋₆alkyl in thepresence of a suitable base, such as for example triethylamine, and asuitable solvent, such as for example dichloromethane.

Compounds of formula (I) wherein R¹ or R³ represents C₁₋₆alkylsubstituted with halo, can be converted into a compound of formula (I)wherein R¹ or R³ represent C₁₋₆alkyl substituted with NR⁴R⁵ or NRo¹R¹¹,by reaction with NHR⁴R⁵or NHR¹⁰R¹¹, either using such amino in largeexcess or in the presence of a suitable base, such as for example K₂CO₃,and a suitable solvent, such as for example acetonitrile,N,N-dimethylacetamide or 1-methyl-pyrrolidinone.

Compounds of formula (I) wherein R¹ represents hydrogen, can beconverted into a compound of formula (I) wherein R¹ representspolyhaloC₁₋₆alkyl or polyhydroxyC₁₋₆alkyl or C₁₋₆alkyl or—S(═O)₂—NR¹⁴R¹⁵ or —S(═O)₂—C₁₋₆alkyl, by reaction withpolyhaloC₁₋₆alkyl-W or polyhydroxyC₁₋₆alkyl-W or C₁₋₆alkyl-W orW—S(═O)₂—NR¹⁴R¹⁵ or W—S(═O)₂—C₁₋₆alkyl, wherein W represents a suitableleaving group, such as for example halo, e.g. bromo and the like, in thepresence of a suitable base, such as for example sodium hydride or K₂CO₃or triethylamine or 4-dimethylamino-pyridine or diisopropylamine, and asuitable solvent, such as for example N,N-dimethylformamide oracetonitrile or dichloromethane.

Compounds of formula (I) wherein R¹ represents hydrogen can also beconverted into a compound of formula (I) wherein R¹ representsC₁₋₆alkyl-OH, by reaction with W—C₁₋₆alkyl-O—Si(CH₃)₂(C(CH₃)₃) in thepresence of a suitable base, such as for example sodium hydride, and asuitable solvent, such as for example N,N-dimethylformamide. Compoundsof formula (I) wherein R¹ represents hydrogen, can also be convertedinto compound of formula (I) wherein R¹ represents ethyl substitutedwith —S(═O)₂—C₁₋₆alkyl, by reaction with C₁₋₆alkyl-vinylsulfone, in thepresence of a suitable base, such as for example triethylamine, and asuitable solvent, such as for example an alcohol, e.g. methanol or byreaction with C₁₋₆alkyl-2-bromoethylsulfone in the presence of asuitable deprotonating agent, such as for example NaH, and a suitablesolvent, such as for example dimethylormamide.

Compounds of formula (I) wherein R¹ represents hydrogen can also beconverted into a compound of formula (I) wherein R¹ represents—CH₂—CHOH—CH₂

by reaction with

in the presence of a suitable base, such as for example sodium hydride,and a suitable solvent, such as for example N,N-dimethylformamide,wherein

represents a suitable nitrogen containing ring within the definition ofR⁶.

Compounds of formula (I) wherein R¹ represents C₁₋₆alkyl substitutedwith R⁶ wherein said R⁶ is substituted with —C(═O)—O—C₁₋₆alkyl or—S(═O)₂—NR¹⁴R¹⁵ or wherein R³ represents C₁₋₆alkyl substituted with R⁹wherein said R⁹ is substituted with —C(═O)—O—C₁₋₆alkyl or—S(═O)₂—NR¹⁴R¹⁵, can be converted into a compound of formula (I) whereinthe R⁶ or R⁹ is unsubstituted, by reaction with a suitable acid, such asfor example HCl and a suitable solvent, such as for example dioxane,acetonitrile or an alcohol, e.g. isopropylalcohol. Compounds of formula(I) wherein R¹ represents C₁₋₆alkyl substituted with R⁶ wherein said R⁶is a ring moiety comprising a nitrogen atom which is substituted with—CH₂—OH or wherein R³ represents C₁₋₆alkyl substituted with R⁹ whereinsaid R⁹ is a ring moiety comprising a nitrogen atom which is substitutedwith —CH₂—OH, can be converted into a compound of formula (I) whereinthe R⁶ or R⁹ is unsubstituted, by reaction with sodium hydroxide, in thepresence of a suitable solvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein R¹ represents C₁₋₆alkyl substitutedwith R⁶ or R³ represents C₁₋₆alkyl substituted with R⁹, wherein said R⁶or said R⁹ is unsubstituted, can be converted into a compound of formula(I) wherein said R⁶ or said R⁹ is substituted with C₁₋₆alkyl, byreaction with W—C₁₋₆alkyl wherein W is as defined above, in the presenceof a suitable base. Such as for example sodium hydride, and a suitablesolvent, such as for example N,N-dimethylformamide.

Compounds of formula (I) wherein R¹ or R³ represent hydroxyC₁₋₆alkyl,can be converted into the corresponding carbonyl compound, by reactionwith dess-Martin-periodinane, in the presence of a suitable solvent,such as for example dichloromethane.

Compounds of formula (I) wherein R¹ represents C₁₋₆alkyl substitutedwith R⁶ or R³ represents C₁₋₆alkyl substituted with R⁹, wherein said R⁶or said R⁹ is substituted with C₁₋₆alkyl-halo, can be converted into acompound of formula (I) wherein said R⁶ or said R⁹ is substituted withC₁₋₆alkyl-CN, by reaction with sodium cyanide, in the presence of asuitable solvent, such as for example water or an alcohol, e.g. ethanol.

Compounds of formula (I) wherein R¹ represents C₁₋₆alkyl substitutedwith R⁶ wherein said R⁶ is unsubstituted or wherein R³ representsC₁₋₆alkyl substituted with R⁹ wherein said R⁹ is unsubstituted, can beconverted into a compound of formula (I) wherein R⁶ or R⁹ is substitutedwith —CH₃ or —CH(CH₃)₂, by reaction with formaldehyde or acetone andNaBH₃CN, in the presence of a suitable solvent, such as for exampletetrahydrofuran or an alcohol, e.g. methanol.

Compounds of formula (I) wherein R¹ contains a R⁶ substituentsubstituted with OH or wherein R³ contains a R⁹ substituent substitutedwith OH, can be converted into a compound of formula (I) wherein the R⁶or R⁹ substituent is substituted with C₁₋₆alkyloxy, by reaction withW—C₁₋₆alkyl, in the presence of a suitable base, such as for examplesodium hydride, and a suitable solvent, such as for exampleN,N-dimethylformamide.

Compounds of formula (I) wherein R¹ contains a R⁶ substituentsubstituted with C₁₋₆alkyloxy or wherein R³ contains a R⁹ substituentsubstituted with C₁₋₆alkyloxy, can be converted into a compound offormula (I) wherein the R⁶ or R⁹ substituent is substituted with —OH byreaction with a suitable acid, such as for example hydrochloric acid.

Compounds of formula (I) wherein R¹ contains a R⁶ substituentsubstituted with halo or wherein R³ contains a R⁹ substituentsubstituted with halo can be converted into a compound of formula (I)wherein the R⁶ or R⁹ substituent is substituted with —NR¹⁴R¹⁵ byreaction with NHR¹⁴R¹⁵ in a suitable sovent, such as for example1-methyl-pyrrolidinone.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith —C(═O)—O—C₁₋₆alkyl, can be converted into a compound of formula (I)wherein R³ represents C₁₋₆alkyl substituted with COOH, by reaction withLiOH in the presence of a suitable solvent, such as for exampletetrahydrofuran. Said compounds of formula (I) wherein R³ representsC₁₋₆alkyl substituted with COOH, can be converted into a compound offormula (I) wherein R³ represents C₁₋₆alkyl substituted with —C(═O)—NH₂or —C(═O)—NHCH₃ or —C(═O)NR¹¹R¹¹, by reaction with NH(Si(CH₃)₃)₂ orMeNH₃ ⁺Cl⁻ or NHR¹⁰R¹¹ in the presence of suitable peptide couplingreagents such as for example1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl and1-hydroxybenzotriazole, a suitable base, such as for exampletriethylamine and a suitable solvent such as for example dichloromethaneor N,N-dimethylformamide. Compounds of formula (I) wherein R³ representsC₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl, can also be convertedinto a compound of formula (I) wherein R³ represents C₁₋₆alkylsubstituted with 2-imidazolyl, by reaction under N₂ with ethylenediamineand trimethylaluminium in the presence of a suitable solvent, such asfor example toluene and heptane. This compound of formula (I) wherein R³represents C₁₋₆alkyl substituted with 2-imidazolyl, can be convertedinto a compound of formula (I) wherein R³ represents C₁₋₆alkylsubstituted with —C(═O)—NH—(CH₂)₂—NH₂ by reaction with sodium hydroxide.Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith COOH, can also be converted into a compound of formula (I) whereinR³ represents C₁₋₆alkyl substituted with —C(═O)—N(CH₃)(OCH₃) by reactionwith dimethylhydroxylamine, in the presence of carbonyldiimidazole and asuitable solvent, such as for example dichloromethane.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith

can be converted into a compound of formula (I) wherein R³ representsC₁₋₆alkyl substituted with 20H's, by reaction with a suitable acid, suchas for example trifluoroacetic acid, and a suitable solvent, such as forexample dioxane or water. These compounds of formula (I) wherein R³represents C₁₋₆alkyl substituted with

can also be converted into a compound of formula (I) wherein R³represents C₁₋₆alkyl substituted with OH and NR¹⁰R¹¹, by reaction withNH₂R¹⁰R¹¹ optionally in salt form, such as for example NHR¹⁰R¹¹⁺Cl⁻,optionally in the presence of a suitable base, such as for examplesodium hydride or Na₂CO₃ or triethylamine or KI, and in the presence ofa suitable solvent, such as for example N,N-dimethylformamide or analcohol, e.g. 1-butanol or ethanol.

Compounds of formula (I) wherein R³ represents C₁₋₃alkyl substitutedwith —C(═O)—O—C₁₋₆alkyl, can be converted into a compound of formula (I)wherein R³ represents C₁₋₃alkyl substituted with —C(CH₃)₂—OH, byreaction with iodomethane and Mg powder, in the presence of a suitablesolvent, such as for example diethylether or tetrahydrofuran.

Compounds of formula (I) wherein R³ represents C₁₋₅alkyl substitutedwith —C(═O)—O—C₁₋₆alkyl, can be converted into a compound of formula (I)wherein R³ represents C₁₋₆alkyl substituted with —OH, by reaction withLiAlH₄ in a suitable solvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein R³ represents C₁₋₅alkyl substitutedwith —OH, can be converted into a compound of formula (I) wherein R³represents C₁₋₅alkyl substituted with —O—C(═O)—C₁₋₆alkyl by reactionwith Cl—C(═O)—C₁₋₆alkyl in the presence of a suitable base, such as forexample NaH, and a suitable solvent, such as for exampletetrahydrofuran.

Compounds of formula (I) wherein R³ represents —CH₂—CH═CH₂, can beconverted into a compound of formula (I) wherein R³ represents—CH₂—CHOH—CH₂—OH, by reaction with potassium permanganate, and asuitable solvent, such as for example acetone or water.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith —C(═O)—C₁₋₄alkyl, can be converted into a compound of formula (I)wherein R³ represents C₁₋₆alkyl substituted with —C(C₁₋₄alkyl)═N—OH, byreaction with hydroxylamine, in the presence of a suitable base, such asfor example pyridine, and a suitable solvent, such as for example analcohol, e.g. ethanol.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith NH₂, can be converted into a compound of formula (I) wherein R³represents C₁₋₆alkyl substituted with —NH—C(═O)—R⁶ or with—NH—C(═O)—C₁₋₆alkyl or with —NH—C(═O)-polyhydroxyC₁₋₆alkyl or with—NH—C(═O)-polyhaloC₁₋₆alkyl or with—NH—C(═O)-polyhydroxypolyhaloCvalkyl, by reaction with the correspondingCOOH analogue, e.g. R⁶—COOH or CF₃—C(CH₃)(OH)—COOH and the like, in thepresence of suitable peptide coupling reagents such as1-hydroxy-benzotriazole and 1-(3-dimethylamino)propyl)carbodiimideoptionally in the presence of a suitable base, such as for exampletriethylamine. Said compounds of formula (I) wherein R³ representsC₁₋₆alkyl substituted with NH₂, can also be converted into a compound offormula (I) wherein R³ represents C₁₋₆alkyl substituted withNH—C(═O)—CF₃, by reaction with trifluoroacetic anhydride, in thepresence of a suitable base, such as for example triethylamine, and asuitable solvent, such as for example tetrahydrofuran. Said compounds offormula (I) wherein R³ represents C₁₋₆alkyl substituted with NH₂, canalso be converted into a compound of formula (I) wherein R³ representsC₁₋₆alkyl substituted with —NH-polyhaloC₁₋₆alkyl, e.g.—NH—CH₂—CH₂—F, byreaction with polyhaloC₁₋₆alkyl-W, with W as defined above, e.g.iodo-2-fluoroethane, in the presence of a suitable base, such as forexample K₂CO₃, and a suitable solvent, such as for exampleN,N-dimethylformamide or dioxane.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith cyano, can be converted into a compound of formula (I) wherein R³represents C₁₋₆alkyl substituted with tetrazolyl by reaction with sodiumazide, and NH₄ ⁺Cl⁻ in the presence of a suitable solvent, such as forexample N,N-dimethylformamide.

Compounds of formula (I) wherein R³ represents —CH₂—C—CH, can beconverted into a compound of formula (I) wherein R³ represents

by reaction with ethyl azidoacetate in the presence of CuI and asuitable base, such as for example diisopropylamine, and a suitablesolvent, such as for example tetraydrofuran.

Compounds of formula (I) wherein R³ represents —CH₂—C≡CH, can beconverted into a compound of formula (I) wherein R³ represents

by reaction with sodium azide and formaldehyde, in the presence of asuitable catalyst, such as for example CuSO₄ and sodium L ascorbate, asuitable acid, such as for example acetic acid, and a suitable solvent,such as for example dioxane.

Compounds of formula (I) wherein R³ represent C₂₋₆alkynyl, can beconverted into a compound of formula (I) wherein R³ representsC₂₋₆alkynyl substituted with R⁹, by reaction with W—R⁹ wherein W is asdefined above, in the presence of a suitable catalyst, such as forexample dichlorobis(triphenylphosphine)palladium, a suitable co-catalystsuch as CuI, a suitable base, such as for example triethylamine, and asuitable solvent, such as for example dimethylsulfoxide.

Compounds of formula (I) wherein R³ comprises R⁹ substituted with halo,can be converted into a compound of formula (I) wherein R³ comprises R⁹substituted with —NR¹⁴R¹⁵ by reaction with NHR¹⁴R¹⁵ in the presence of asuitable solvent, such as for example 1-methyl-2-pyrrolidinone.

Compounds of formula (I) wherein R³ comprises C₂₋₆alkynyl, can behydrogenated into a compound of formula (I) wherein R³ comprisesC₂₋₆alkyl in the presence of a suitable catalyst, such as for examplepalladium on charcoal, and a suitable solvent, such as for exampleethylacetate.

Compounds of formula (I) wherein R³ comprises C₂₋₆alkynyl, can behydrogenated into a compound of formula (I) wherein R³ comprisesC₂₋₆alkenyl in the presence of a suitable catalyst, such as for exampleLindlar catalyst, and a suitable solvent, such as for exampleethylacetate.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith —P(═O)(OC₁₋₆alkyl)₂ can be converted into a compound of formula (I)wherein R³ represents C₁₋₆alkyl substituted with —P(═O)(OH)₂ by reactionwith bromotrimethylsilane in the presence of a suitable solvent, such asfor example dichloromethane.

Compounds of formula (I) wherein the R⁹ substituent is substituted with═O, can be converted into the corresponding reduced R⁹ substituent byreaction with a suitable reducing agent, such as for example LiAlH₄ in asuitable solvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein R³ comprises —NHR¹⁰ can be convertedinto a compound of formula (I) wherein R³ comprises—NR¹⁰—(C═O)-optionally substituted C₁₋₆alkyl, by reaction with thecorresponding W—(C═O)-optionally substituted C₁₋₆alkyl wherein Wrepresents a suitable leaving group, such as for example halo, e.g.chloro and the like, in the presence of a suitable base, such as forexample triethylamine, and a suitable solvent, such as for exampleacetonitrile.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith NRo¹(benzyl) can be converted into a compound of formula (I)wherein R³ represents C₁₋₆alkyl substituted with NHR¹⁰, by reaction with1-chloroethylchloroformate in the presence of a suitable solvent, suchas for example dichloromethane

Compounds of formula (I) wherein R¹ represents unsubstituted piperidine,can be converted into a compound of formula (I) wherein R¹ represents1-methyl-piperidine, by reaction with iodomethane in the presence of asuitable base, such as for example potassium carbonate, and a suitablesolvent, such as for example acetonitrile.

Compounds of formula (I) wherein R¹ represents hydrogen can be convertedinto a compound of formula (I) wherein R¹ represents optionallysubstituted C₁₋₆alkyl, by reaction with optionally substitutedC₁₋₆alkyl-W wherein W represents a suitable leaving group, such as forexample halo, e.g. bromo and the like, in the presence of a suitablebase, such as for example potassium carbonate, and a suitable solvent,such as for example acetonitrile.

Compounds of formula (I) wherein R² represents halo, e.g. bromo, can beconverted into a compound of formula (I) wherein R² represents cyano, byreaction with zinc cyanide, in the presence of a suitable catalyst, suchas for example Pd₂(dba)₃ and a suitable ligand, such as for example1,1-bis(diphenylphosphino)ferrocene, in the presence of a suitablesolvent, such as for example N,N-dimethylformamide.

Said R² substituent being cyano can be converted into —CH₂—NH₂ byhydrogenation in the presence of NH₃ and Nickel.

Compounds of formula (I) wherein R² represents —OCH₃ can be convertedinto a compounds of formula (I) wherein R² represents —OH by reactionwith boron tribromide in the presence of a suitable solvent, such as forexample dichloromethane.

Compounds of formula (I) wherein R² represents —OH can be converted intoa compounds of formula (I) wherein R² represents —OCH₃ by reaction withmethyl iodine in the presence of a suitable base, such as for examplepotassium carbonate, and a suitable solvent, such as for exampleN,N-dimethylformamide.

Compounds of formula (I) wherein R² represents hydrogen, can beconverted into a compound of formula (I) wherein R² represents —CHOH—CF₃by reaction with trifluoroacetaldehyde methyl hemiketal.

A further aspect of the invention is a process for the preparation of acompound of formula (I) as defined herein, which process comprises:

(i) deprotecting a compound of formula (XXX) wherein P represents asuitable protective group, such as for example a butyloxycarbonyl-group(—CO₂C(CH₃)₃) in the presence of a suitable acid, such as for exampleHCl or trifluoroacetic acid;

(ii) the reaction of a compound of the formula (IX) or (IX′):

or a protected form thereof, with an appropriately substituted amine ora reactive derivative thereof, such as for example NHR¹⁰R¹¹(X), NHR¹⁰P(X-a) or H-

(XXI), for example in a sealed vessel, in the presence of a suitablebase, such as for example sodium hydride and/or in the presence orabsence of a solvent such as acetonitrile, N,N-dimethylformamide orN,N-dimethylacetamide; or(iii) the reaction of a compound of the formula (VI):

or a protected form thereof, with a compound of formulaW₆—C₁₋₆alkyl-NR¹⁰P wherein P represents a suitable protective group andW₆ represents a suitable leaving group, such as for example halo, e.g.bromo and the like, or —O—S(═O)₂—CH₃, in the presence of a suitablebase, such as for example sodium hydride, and a suitable solvent, e.g.N,N-dimethylformamide or N,N-dimethylacetamide, followed by removing Pand optionally removing any further protecting group present; or(iv) the reaction of a compound of the formula (VI):

or a protected thereof, with a compound of formula W₆—C₁₋₆alkyl-NHR¹⁰wherein W₆ represents a suitable leaving group, such as for examplehalo, e.g. bromo and the like, or —O—S(═O)₂—CH₃, in the presence of asuitable base, such as for example sodium hydride, and a suitablesolvent, e.g. N,N-dimethylformamide or N,N-dimethylacetamide;(v) the reaction of a compound of formula (XXXVI)

with hydrazine in the presence of a suitable solvent, such as forexample an alcohol, e.g. ethanol;(vi) the reaction of a compound of formula (IX-1) wherein R^(u)represents —O—S(═O)₂—CH₃,

with an intermediate of formula (X) in the presence of a suitablesolvent, such as for example acetonitrile;(vii) the reaction of a compound of formula (VI)

with an intermediate of formula W₁₁—R^(3b) wherein R^(3b) representsoptionally substituted C₂₋₆alkynyl and W₁₁ represents a suitable leavinggroup such as for example halo, e.g. chloro, or —O—S(═O)₂—CH₃, in thepresence of a suitable base, such as for example NaH, and a suitablesolvent, such as for example N,N-dimethylformamide;(viii) the reaction of a compound of formula (VIII′) wherein R^(x) andR^(y) represent Cl₁₋₄alkyl, and R^(z) represent C₁₋₄alkyl or phenyl,

with a suitable acid, such as for example trifluoroacetic acid, in thepresence of a suitable solvent, such as for example tetrahydrofuran;(viii) deprotecting a compound of formula (XXXXII)

in the presence of a suitable base, such as for example K₂CO₃, and asuitable solvent, such as for example an alcohol, e.g. methanol and thelike;(ix) the reaction of a compound of formula (VI)

with di(C₁₋₆alkyl)vinylphosphonate in the presence of a suitablecatalyst, such as for example tri-N-butylphosphine, and a suitablesolvent, such as for example acetonitrile;(x) deprotecting a compound of formula (XXXXI)

in the presence of a suitable base, such as for example K₂CO₃, and asuitable solvent, such as for example an alcohol, e.g. methanol and thelike;(xi) the reaction of a compound of formula (XIX) with a compound offormula (III)

in the presence of a suitable catalyst, such as for exampletetrakis(triphenyl)phosphine palladium or Pd₂(dba)₃(tris(dibenzylideneacetone) dipalladium (0)), a suitable ligand, such as2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, a suitable base, suchas for example Na₂CO₃ or K₃PO₄, and a suitable solvent, such as forexample ethylene glycol dimethylether or dioxane or water;(xii) the reaction of a compound of formula (XX) wherein R^(3a)represents optionally substituted C₁₋₆alkyl, with a compound of formula(XIV)

in the presence of a suitable catalyst, such as for example palladium(II) acetate or Pd₂(dba)₃ (tris(dibenzylidene acetone) dipalladium (0)),a suitable ligand such as for example2-dicyclohexylphosphino-tris-isopropyl-biphenyl or1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], asuitable base, such as for example sodium tert-butoxide, and a suitablesolvent, such as for example ethylene glycol dimethylether;(xiii) the reaction of a compound of formula (XXXI)

with W₈—CN, wherein W₈ represents a suitable leaving group, such as forexample halo, e.g. bromo, in the presence of a suitable base, such asfor example NaHCO₃, and a suitable solvent, such as for example water ordioxane;(xiv) the reaction of a compound of formula (XXXV)

with a suitable base, such as for example N,N-diisopropylethylamine andtriethylamine, in the presence of a suitable solvent, such as forexample an alcohol, e.g. methanol;(xv) deprotecting a compound of formula (XXVI) wherein P represents asuitable protective group such as for example —O—Si(CH₃)₂(C(CH₃)₃) or

in the presence of a suitable acid, such as for example HCl ortrifluoroacetic acid, or a suitable de-silylating agent, such as forexample tetrabutyl ammonium fluoride, and a suitable solvent, such as analcohol, e.g. methanol, or tetrahydrofuran;(xvi) the reaction of a compound of formula (XXIX) with a compound offormula (XXI)

in the presence of suitable peptide coupling reagents such as,1-hydroxy-benzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl;(xvii) the reaction of a compound of formula (XXIX)

with NHR⁴R⁵ in the presence of suitable peptide coupling reagents suchas 1-hydroxy-benzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl and a suitable base, such as triethylamine, and asuitable solvent, such as for example dichloromethane;(xviii) reacting the below compound

with NHR⁷R⁸ in the presence of a suitable base, such as for exampleK₂CO₃, and a suitable solvent, such as for example tetrahydrofuran;(xviii) deprotecting the below compound

in the presence of hydrazine monohydrate, and a suitable solvent, suchas for example an alcohol, e.g. ethanol;

wherein R¹, R^(1a), R², R¹⁰, and n are as defined herein; and optionallythereafter converting one compound of the formula (I) into anothercompound of the formula (I).

A further embodiment is a process for synthesis of a compound of formula(VI) wherein:

1) a compound of formula (II) is reacted with an intermediate of formula(III) in the presence of a suitable catalyst, such as for exampletetrakis(triphenylphosphine)palladium (0) or palladium (II) acetate, asuitable base, such as for example sodium carbonate, a suitable ligand,such as for example triphenylphosphine, and a suitable solvent orsolvent mixture, such as for example ethylene glycol dimethylether andwater; wherein W₁ and W₂, each independently represent a suitableleaving group, such as for example halo, e.g. chloro or bromo;and then2) a compound of formula (IV) is reacted with an intermediate of formula(V) in the presence of a suitable catalyst, such as for examplepalladium (II) acetate, a suitable base, such as sodium tert-butoxide orCs₂CO₃, a suitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], and asuitable solvent or solvent mixture, such as for example dioxane orethylene glycol dimethylether and water;wherein optionally the intermediate of formula (II) wherein W₁ is chloroand W₂ is bromo is prepared by reacting 7-bromo-2(1H)-quinoxalinone withphosphorus oxychloride, or alternatively with thionyl chloride andN,N-dimethylformamide in a suitable solvent, such as, for exampletoluene;or vice versa, wherein a compound of formula (II) is reacted with anintermediate of formula (V) first and then reacted with an intermediateof formula (III) using the methods described above.

In a further embodiment the invention provides a novel intermediate. Inone embodiment the invention provides a novel intermediate of formula(II)-(XXXI). In another embodiment the invention provides a novelintermediate of formula (VI) or formula (IX). In another embodiment theinvention provides a compound of formula (I-a)-(I-i).

Pharmaceutically Acceptable Salts, Solvates or Derivatives Thereof.

In this section, as in all other sections of this application, unlessthe context indicates otherwise, references to formula (I) includereferences to all other sub-groups, preferences, embodiments andexamples thereof as defined herein.

Unless otherwise specified, a reference to a particular compound alsoincludes ionic forms, salts, solvates, isomers, tautomers, N-oxides,esters, prodrugs, isotopes and protected forms thereof, for example, asdiscussed below; preferably, the ionic forms, or salts or tautomers orisomers or N-oxides or solvates thereof; and more preferably, the ionicforms, or salts or tautomers or solvates or protected forms thereof,even more preferably the salts or tautomers or solvates thereof. Manycompounds of the formula (I) can exist in the form of salts, for exampleacid addition salts or, in certain cases salts of organic and inorganicbases such as carboxylate, sulphonate and phosphate salts. All suchsalts are within the scope of this invention, and references tocompounds of the formula (I) include the salt forms of the compounds. Itwill be appreciated that references to “derivatives” include referencesto ionic forms, salts, solvates, isomers, tautomers, N-oxides, esters,prodrugs, isotopes and protected forms thereof.

According to one aspect of the invention there is provided a compound asdefined herein or a salt, tautomer, N-oxide or solvate thereof.According to a further aspect of the invention there is provided acompound as defined herein or a salt or solvate thereof. References tocompounds of the formula (I) and sub-groups thereof as defined hereininclude within their scope the salts or solvates or tautomers orN-oxides of the compounds.

The salt forms of the compounds of the invention are typicallypharmaceutically acceptable salts, and examples of pharmaceuticallyacceptable salts are discussed in Berge et al. (1977) “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, saltsthat are not pharmaceutically acceptable may also be prepared asintermediate forms which may then be converted into pharmaceuticallyacceptable salts. Such non-pharmaceutically acceptable salts forms,which may be useful, for example, in the purification or separation ofthe compounds of the invention, also form part of the invention.

The salts of the present invention can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods such as methods described in Pharmaceutical Salts: Properties,Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth(Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.Generally, such salts can be prepared by reacting the free acid or baseforms of these compounds with the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally, nonaqueousmedia such as ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are used. The compounds of the invention may exist as mono-or di-salts depending upon the pKa of the acid from which the salt isformed.

Acid addition salts may be formed with a wide variety of acids, bothinorganic and organic. Examples of acid addition salts include saltsformed with an acid selected from the group consisting of acetic,2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic),L-aspartic, benzenesulphonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulphonic, (+)-(1S)-camphor-10-sulphonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric,ethane-1,2-disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic,formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic,glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic),α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic,isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic), lactobionic,maleic, malic, (−)-L-malic, malonic, (±)-DL-mandelic, methanesulphonic,naphthalenesulphonic (e.g. naphthalene-2-sulphonic),naphthalene-1,5-disulphonic, 1-hydroxy-2-naphthoic, nicotinic, nitric,oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic,L-pyroglutamic, pyruvic, salicylic, 4-amino-salicylic, sebacic, stearic,succinic, sulphuric, tannic, (+)-L-tartaric, thiocyanic,toluenesulphonic (e.g. p-toluenesulphonic), undecylenic and valericacids, as well as acylated amino acids and cation exchange resins.

One particular group of salts consists of salts formed from acetic,hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic,succinic, maleic, malic, isethionic, fumaric, benzenesulphonic,toluenesulphonic, methanesulphonic (mesylate), ethanesulphonic,naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic,glucuronic and lactobionic acids. Another group of acid addition saltsincludes salts formed from acetic, adipic, ascorbic, aspartic, citric,DL-Lactic, fumaric, gluconic, glucuronic, hippuric, hydrochloric,glutamic, DL-malic, methanesulphonic, sebacic, stearic, succinic andtartaric acids.

If the compound is anionic, or has a functional group which may beanionic (e.g., —COOH may be —COO—), then a salt may be formed with asuitable cation. Examples of suitable inorganic cations include, but arenot limited to, alkali metal ions such as Na⁺ and K⁺, alkaline earthmetal cations such as Ca²⁺ and Mg²⁺, and other cations such as Al³⁺.Examples of suitable organic cations include, but are not limited to,ammonium ion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺,NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺).

Examples of some suitable substituted ammonium ions are those derivedfrom: ethylamine, diethylamine, dicyclohexylamine, triethylamine,butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine,benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, aswell as amino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

Where the compounds of the formula (I) contain an amine function, thesemay form quaternary ammonium salts, for example by reaction with analkylating agent according to methods well known to the skilled person.Such quaternary ammonium compounds are within the scope of formula (I).Compounds of the formula (I) containing an amine function may also formN-oxides. A reference herein to a compound of the formula (I) thatcontains an amine function also includes the N-oxide. Where a compoundcontains several amine functions, one or more than one nitrogen atom maybe oxidised to form an N-oxide. Particular examples of N-oxides are theN-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containingheterocycle. N-Oxides can be formed by treatment of the correspondingamine with an oxidizing agent such as hydrogen peroxide or a per-acid(e.g. a peroxycarboxylic acid), see for example Advanced OrganicChemistry, by Jerry March, 4^(th) Edition, Wiley Interscience, pages.More particularly, N-oxides can be made by the procedure of L. W. Deady(Syn. Comm. (1977), 7, 509-514) in which the amine compound is reactedwith m-chloroperoxybenzoic acid (MCPBA), for example, in an inertsolvent such as dichloromethane.

The compounds of the invention may form solvates, for example with water(i.e., hydrates) or common organic solvents. As used herein, the term“solvate” means a physical association of the compounds of the presentinvention with one or more solvent molecules. This physical associationinvolves varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instances the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. The term“solvate” is intended to encompass both solution-phase and isolatablesolvates. Non-limiting examples of suitable solvates include compoundsof the invention in combination with water, isopropanol, ethanol,methanol, DMSO, ethyl acetate, acetic acid or ethanolamine and the like.The compounds of the invention may exert their biological effects whilstthey are in solution.

Solvates are well known in pharmaceutical chemistry. They can beimportant to the processes for the preparation of a substance (e.g. inrelation to their purification, the storage of the substance (e.g. itsstability) and the ease of handling of the substance and are oftenformed as part of the isolation or purification stages of a chemicalsynthesis. A person skilled in the art can determine by means ofstandard and long used techniques whether a hydrate or other solvate hasformed by the isolation conditions or purification conditions used toprepare a given compound. Examples of such techniques includethermogravimetric analysis (TGA), differential scanning calorimetry(DSC), X-ray crystallography (e.g. single crystal X-ray crystallographyor X-ray powder diffraction) and Solid State NMR (SS-NMR, also known asMagic Angle Spinning NMR or MAS-NMR). Such techniques are as much a partof the standard analytical toolkit of the skilled chemist as NMR, IR,HPLC and MS. Alternatively the skilled person can deliberately form asolvate using crystallisation conditions that include an amount of thesolvent required for the particular solvate. Thereafter the standardmethods described above, can be used to establish whether solvates hadformed. Also encompassed by formula (I) are any complexes (e.g.inclusion complexes or clathrates with compounds such as cyclodextrins,or complexes with metals) of the compounds.

Furthermore, the compounds of the present invention may have one or morepolymorph (crystalline) or amorphous forms and as such are intended tobe included in the scope of the invention.

Compounds of the formula (I) may exist in a number of differentgeometric isomeric, and tautomeric forms and references to compounds ofthe formula (I) include all such forms. For the avoidance of doubt,where a compound can exist in one of several geometric isomeric ortautomeric forms and only one is specifically described or shown, allothers are nevertheless embraced by formula (I). Other examples oftautomeric forms include, for example, keto-, enol-, and enolate-forms,as in, for example, the following tautomeric pairs: keto/enol(illustrated below), imine/enamine, amide/imino alcohol,amidine/enediamines, nitroso/oxime, thioketone/enethiol, andnitro/aci-nitro.

Where compounds of the formula (I) contain one or more chiral centres,and can exist in the form of two or more optical isomers, references tocompounds of the formula (I) include all optical isomeric forms thereof(e.g. enantiomers, epimers and diastereoisomers), either as individualoptical isomers, or mixtures (e.g. racemic mixtures) of two or moreoptical isomers, unless the context requires otherwise. The opticalisomers may be characterised and identified by their optical activity(i.e. as + and − isomers, or d and I isomers) or they may becharacterised in terms of their absolute stereochemistry using the “Rand S” nomenclature developed by Cahn, Ingold and Prelog, see AdvancedOrganic Chemistry by Jerry March, 4^(th) Edition, John Wiley & Sons, NewYork, 1992, pages 109-114, and see also Cahn, Ingold & Prelog (1966)Angew. Chem. Int. Ed. Engl., 5, 385-415. Optical isomers can beseparated by a number of techniques including chiral chromatography(chromatography on a chiral support) and such techniques are well knownto the person skilled in the art. As an alternative to chiralchromatography, optical isomers can be separated by formingdiastereoisomeric salts with chiral acids such as (+)-tartaric acid,(−)-pyroglutamic acid, (−)-di-toluoyl-L-tartaric acid, (+)-mandelicacid, (−)-malic acid, and (−)-camphorsulphonic, separating thediastereoisomers by preferential crystallisation, and then dissociatingthe salts to give the individual enantiomer of the free base.

Where compounds of the formula (I) exist as two or more optical isomericforms, one enantiomer in a pair of enantiomers may exhibit advantagesover the other enantiomer, for example, in terms of biological activity.Thus, in certain circumstances, it may be desirable to use as atherapeutic agent only one of a pair of enantiomers, or only one of aplurality of diastereoisomers. Accordingly, the invention providescompositions containing a compound of the formula (I) having one or morechiral centres, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%,80%, 85%, 90% or 95%) of the compound of the formula (I) is present as asingle optical isomer (e.g. enantiomer or diastereoisomer). In onegeneral embodiment, 99% or more (e.g. substantially all) of the totalamount of the compound of the formula (I) may be present as a singleoptical isomer (e.g. enantiomer or diastereoisomer).

The compounds of the invention include compounds with one or moreisotopic substitutions, and a reference to a particular element includeswithin its scope all isotopes of the element. For example, a referenceto hydrogen includes within its scope ¹H, ²H (D), and ³H (T). Similarly,references to carbon and oxygen include within their scope respectively¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. The isotopes may be radioactive ornon-radioactive. In one embodiment of the invention, the compoundscontain no radioactive isotopes. Such compounds are preferred fortherapeutic use. In another embodiment, however, the compound maycontain one or more radioisotopes. Compounds containing suchradioisotopes may be useful in a diagnostic context.

Esters such as carboxylic acid esters and acyloxy esters of thecompounds of formula (I) bearing a carboxylic acid group or a hydroxylgroup are also embraced by formula (I). In one embodiment of theinvention, formula (I) includes within its scope esters of compounds ofthe formula (I) bearing a carboxylic acid group or a hydroxyl group. Inanother embodiment of the invention, formula (I) does not include withinits scope esters of compounds of the formula (I) bearing a carboxylicacid group or a hydroxyl group. Examples of esters are compoundscontaining the group —C(═O)OR, wherein R is an ester substituent, forexample, a C₁₋₆ alkyl group, a heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₆ alkyl group. Particular examples of estergroups include, but are not limited to, —C(═O)OCH₃, —C(═O)OCH₂CH₃,—C(═O)OC(CH₃)₃, and —C(═O)OPh. Examples of acyloxy (reverse ester)groups are represented by —OC(═O)R, wherein R is an acyloxy substituent,for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇ alkyl group. Particular examples ofacyloxy groups include, but are not limited to, —OC(═O)CH₃ (acetoxy),—OC(═O)CH₂CH₃, —OC(═O)C(CH₃)₃, —OC(═O)Ph, and —OC(═O)CH₂Ph.

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). By “prodrugs” ismeant for example any compound that is converted in vivo into abiologically active compound of the formula (I). During metabolism, theester group (—C(═O)OR) is cleaved to yield the active drug. Such estersmay be formed by esterification, for example, of any of the carboxylicacid groups (—C(═O)OH) in the parent compound, with, where appropriate,prior protection of any other reactive groups present in the parentcompound, followed by deprotection if required.

Examples of such metabolically labile esters include those of theformula —C(═O)OR wherein R is: C₁₋₆alkyl (e.g., -Me, -Et, -nPr, -iPr,-nBu, -sBu, -iBu, -tBu); C₁₋₆-aminoalkyl [e.g., aminoethyl;2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C₁₋₇alkyl[e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl;1-acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl-carbonyloxyethyl;1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl;1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl;1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl;1-cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy)carbonyloxymethyl; 1-(4-tetrahydropyranyloxy)carbonyloxyethyl;(4-tetrahydropyranyl)carbonyloxymethyl; and1-(4-tetrahydropyranyl)carbonyloxyethyl]. Also, some prodrugs areactivated enzymatically to yield the active compound, or a compoundwhich, upon further chemical reaction, yields the active compound (forexample, as in antigen-directed enzyme pro-drug therapy (ADEPT),gene-directed enzyme pro-drug therapy (GDEPT) and ligand-directed enzymepro-drug therapy (LIDEPT) etc.). For example, the prodrug may be a sugarderivative or other glycoside conjugate, or may be an amino acid esterderivative.

Protein Tyrosine Kinases (PTK)

The compounds of the invention described herein inhibit or modulate theactivity of certain tyrosine kinases, and thus the compounds will beuseful in the treatment or prophylaxis, in particular the treatment, ofdisease states or conditions mediated by those tyrosine kinases, inparticular FGFR.

FGFR

The fibroblast growth factor (FGF) family of protein tyrosine kinase(PTK) receptors regulates a diverse array of physiologic functionsincluding mitogenesis, wound healing, cell differentiation andangiogenesis, and development. Both normal and malignant cell growth aswell as proliferation are affected by changes in local concentration ofFGFs, extracellular signalling molecules which act as autocrine as wellas paracrine factors. Autocrine FGF signalling may be particularlyimportant in the progression of steroid hormone-dependent cancers to ahormone independent state. FGFs and their receptors are expressed atincreased levels in several tissues and cell lines and overexpression isbelieved to contribute to the malignant phenotype. Furthermore, a numberof oncogenes are homologues of genes encoding growth factor receptors,and there is a potential for aberrant activation of FGF-dependentsignalling in human pancreatic cancer (Knights et al., Pharmacology andTherapeutics 2010 125:1 (105-117); Korc M. et al Current Cancer DrugTargets 2009 9:5 (639-651)).

The two prototypic members are acidic fibroblast growth factor (aFGF orFGF1) and basic fibroblast growth factor (bFGF or FGF2), and to date, atleast twenty distinct FGF family members have been identified. Thecellular response to FGFs is transmitted via four types of high affinitytransmembrane protein tyrosine-kinase fibroblast growth factor receptors(FGFR) numbered 1 to 4 (FGFR1 to FGFR4).

Disruption of the FGFR1 pathway should affect tumor cell proliferationsince this kinase is activated in many tumor types in addition toproliferating endothelial cells. The over-expression and activation ofFGFR1 in tumor-associated vasculature has suggested a role for thesemolecules in tumor angiogenesis.

A recent study has shown a link between FGFR1 expression andtumorigenicity in Classic Lobular Carcinomas (CLC). CLCs account for10-15% of all breast cancers and, in general, lack p53 and Her2expression whilst retaining expression of the oestrogen receptor. A geneamplification of 8p12-p11.2 was demonstrated in −50% of CLC cases andthis was shown to be linked with an increased expression of FGFR1.Preliminary studies with siRNA directed against FGFR1, or a smallmolecule inhibitor of the receptor, showed cell lines harbouring thisamplification to be particularly sensitive to inhibition of thissignalling pathway. Rhabdomyosarcoma (RMS) is the most common pediatricsoft tissue sarcoma likely results from abnormal proliferation anddifferentiation during skeletal myogenesis. FGFR1 is over-expressed inprimary rhabdomyosarcoma tumors and is associated with hypomethylationof a 5′ CpG island and abnormal expression of the AKT1, NOG, and BMP4genes.

Fibroblast growth factor receptor 2 has high affinity for the acidicand/or basic fibroblast growth factors, as well as the keratinocytegrowth factor ligands. Fibroblast growth factor receptor 2 alsopropagates the potent osteogenic effects of FGFs during osteoblastgrowth and differentiation. Mutations in fibroblast growth factorreceptor 2, leading to complex functional alterations, were shown toinduce abnormal ossification of cranial sutures (craniosynostosis),implying a major role of FGFR signalling in intramembranous boneformation. For example, in Apert (AP) syndrome, characterized bypremature cranial suture ossification, most cases are associated withpoint mutations engendering gain-of-function in fibroblast growth factorreceptor 2. In addition, mutation screening in patients with syndromiccraniosynostoses indicates that a number of recurrent FGFR2 mutationsaccounts for severe forms of Pfeiffer syndrome. Particular mutations ofFGFR2 include W290C, D321A, Y340C, C342R, C342S, C342W, N549H, K641R inFGFR2.

Several severe abnormalities in human skeletal development, includingApert, Crouzon, Jackson-Weiss, Beare-Stevenson cutis gyrata, andPfeiffer syndromes are associated with the occurrence of mutations infibroblast growth factor receptor 2. Most, if not all, cases of PfeifferSyndrome (PS) are also caused by de novo mutation of the fibroblastgrowth factor receptor 2 gene, and it was recently shown that mutationsin fibroblast growth factor receptor 2 break one of the cardinal rulesgoverning ligand specificity. Namely, two mutant splice forms offibroblast growth factor receptor, FGFR2c and FGFR2b, have acquired theability to bind to and be activated by atypical FGF ligands. This lossof ligand specificity leads to aberrant signalling and suggests that thesevere phenotypes of these disease syndromes result from ectopicligand-dependent activation of fibroblast growth factor receptor 2.

Genetic aberrations of the FGFR3 receptor tyrosine kinase such aschromosomal translocations or point mutations result in ectopicallyexpressed or deregulated, constitutively active, FGFR3 receptors. Suchabnormalities are linked to a subset of multiple myelomas and inbladder, hepatocellular, oral squamous cell carcinoma and cervicalcarcinomas. Accordingly, FGFR3 inhibitors would be useful in thetreatment of multiple myeloma, bladder and cervical carcinomas. FGFR3 isalso over-expressed in bladder cancer, in particular invasive bladdercancer. FGFR3 is frequently activated by mutation in urothelialcarcinoma (UC). Increased expression was associated with mutation (85%of mutant tumors showed high-level expression) but also 42% of tumorswith no detectable mutation showed over-expression, including manymuscle-invasive tumors.

Over expression of FGFR4 has been linked to poor prognosis in bothprostate and thyroid carcinomas. In addition a germline polymorphism(Gly388Arg) is associated with increased incidence of lung, breast,colon, liver (HCC) and prostate cancers. In addition, a truncated formof FGFR4 (including the kinase domain) has also been found to be presentin 40% of pituitary tumours but not present in normal tissue. FGFR4overexpression has been observed in liver, colon and lung tumours. FGFR4has been implicated in colorectal and liver cancer where expression ofits ligand FGF19 is frequently elevated.

Fibrotic conditions are a major medical problem resulting from abnormalor excessive deposition of fibrous tissue. This occurs in many diseases,including liver cirrhosis, glomerulonephritis, pulmonary fibrosis,systemic fibrosis, rheumatoid arthritis, as well as the natural processof wound healing. The mechanisms of pathological fibrosis are not fullyunderstood but are thought to result from the actions of variouscytokines (including tumor necrosis factor (TNF), fibroblast growthfactors (FGF's), platelet derived growth factor (PDGF) and transforminggrowth factor beta. (TGFβ) involved in the proliferation of fibroblastsand the deposition of extracellular matrix proteins (including collagenand fibronectin). This results in alteration of tissue structure andfunction and subsequent pathology.

A number of preclinical studies have demonstrated the up-regulation offibroblast growth factors in preclinical models of lung fibrosis. TGF31and PDGF have been reported to be involved in the fibrogenic process andfurther published work suggests the elevation of FGF's and consequentincrease in fibroblast proliferation, may be in response to elevatedTGFβ1. The potential therapeutic benefit of targeting the fibroticmechanism in conditions such as idiopathic pulmonary fibrosis (IPF) issuggested by the reported clinical effect of the anti-fibrotic agentpirfenidone. Idiopathic pulmonary fibrosis (also referred to asCryptogenic fibrosing alveolitis) is a progressive condition involvingscarring of the lung. Gradually, the air sacs of the lungs becomereplaced by fibrotic tissue, which becomes thicker, causing anirreversible loss of the tissue's ability to transfer oxygen into thebloodstream. The symptoms of the condition include shortness of breath,chronic dry coughing, fatigue, chest pain and loss of appetite resultingin rapid weight loss. The condition is extremely serious withapproximately 50% mortality after 5 years.

As such, the compounds which inhibit FGFR will be useful in providing ameans of preventing the growth or inducing apoptosis in tumours,particularly by inhibiting angiogenesis. It is therefore anticipatedthat the compounds will prove useful in treating or preventingproliferative disorders such as cancers. In particular tumours withactivating mutants of receptor tyrosine kinases or upregulation ofreceptor tyrosine kinases may be particularly sensitive to theinhibitors. Patients with activating mutants of any of the isoforms ofthe specific RTKs discussed herein may also find treatment with RTKinhibitors particularly beneficial.

Vascular Endothelial Growth Factor (VEGFR)

Chronic proliferative diseases are often accompanied by profoundangiogenesis, which can contribute to or maintain an inflammatory and/orproliferative state, or which leads to tissue destruction through theinvasive proliferation of blood vessels.

Angiogenesis is generally used to describe the development of new orreplacement blood vessels, or neovascularisation. It is a necessary andphysiological normal process by which vasculature is established in theembryo. Angiogenesis does not occur, in general, in most normal adulttissues, exceptions being sites of ovulation, menses and wound healing.Many diseases, however, are characterized by persistent and unregulatedangiogenesis. For instance, in arthritis, new capillary blood vesselsinvade the joint and destroy cartilage. In diabetes (and in manydifferent eye diseases), new vessels invade the macula or retina orother ocular structures, and may cause blindness. The process ofatherosclerosis has been linked to angiogenesis. Tumor growth andmetastasis have been found to be angiogenesis-dependent.

The recognition of the involvement of angiogenesis in major diseases hasbeen accompanied by research to identify and develop inhibitors ofangiogenesis. These inhibitors are generally classified in response todiscrete targets in the angiogenesis cascade, such as activation ofendothelial cells by an angiogenic signal; synthesis and release ofdegradative enzymes; endothelial cell migration; proliferation ofendothelial cells; and formation of capillary tubules. Therefore,angiogenesis occurs in many stages and attempts are underway to discoverand develop compounds that work to block angiogenesis at these variousstages.

There are publications that teach that inhibitors of angiogenesis,working by diverse mechanisms, are beneficial in diseases such as cancerand metastasis, ocular diseases, arthritis and hemangioma.

Vascular endothelial growth factor (VEGF), a polypeptide, is mitogenicfor endothelial cells in vitro and stimulates angiogenic responses invivo. VEGF has also been linked to inappropriate angiogenesis. VEGFR(s)are protein tyrosine kinases (PTKs). PTKs catalyze the phosphorylationof specific tyrosine residues in proteins involved in cell function thusregulating cell growth, survival and differentiation.

Three PTK receptors for VEGF have been identified: VEGFR-1 (Flt-1);VEGFR-2 (Flk-1 or KDR) and VEGFR-3 (Flt-4). These receptors are involvedin angiogenesis and participate in signal transduction. Of particularinterest is VEGFR-2, which is a transmembrane receptor PTK expressedprimarily in endothelial cells. Activation of VEGFR-2 by VEGF is acritical step in the signal transduction pathway that initiates tumourangiogenesis. VEGF expression may be constitutive to tumour cells andcan also be upregulated in response to certain stimuli. One such stimuliis hypoxia, where VEGF expression is upregulated in both tumour andassociated host tissues. The VEGF ligand activates VEGFR-2 by bindingwith its extracellular VEGF binding site. This leads to receptordimerization of VEGFRs and autophosphorylation of tyrosine residues atthe intracellular kinase domain of VEGFR-2. The kinase domain operatesto transfer a phosphate from ATP to the tyrosine residues, thusproviding binding sites for signalling proteins downstream of VEGFR-2leading ultimately to initiation of angiogenesis.

Inhibition at the kinase domain binding site of VEGFR-2 would blockphosphorylation of tyrosine residues and serve to disrupt initiation ofangiogenesis.

Angiogenesis is a physiologic process of new blood vessel formationmediated by various cytokines called angiogenic factors. Although itspotential pathophysiologic role in solid tumors has been extensivelystudied for more than 3 decades, enhancement of angiogenesis in chroniclymphocytic leukemia (CLL) and other malignant hematological disordershas been recognized more recently. An increased level of angiogenesishas been documented by various experimental methods both in bone marrowand lymph nodes of patients with CLL. Although the role of angiogenesisin the pathophysiology of this disease remains to be fully elucidated,experimental data suggest that several angiogenic factors play a role inthe disease progression. Biologic markers of angiogenesis were alsoshown to be of prognostic relevance in CLL. This indicates that VEGFRinhibitors may also be of benefit for patients with leukemia's such asCLL.

In order for a tumour mass to get beyond a critical size, it mustdevelop an associated vasculature. It has been proposed that targeting atumor vasculature would limit tumor expansion and could be a usefulcancer therapy. Observations of tumor growth have indicated that smalltumour masses can persist in a tissue without any tumour-specificvasculature. The growth arrest of nonvascularized tumors has beenattributed to the effects of hypoxia at the center of the tumor. Morerecently, a variety of proangiogenic and antiangiogenic factors havebeen identified and have led to the concept of the “angiogenic switch,”a process in which disruption of the normal ratio of angiogenic stimuliand inhibitors in a tumor mass allows for autonomous vascularization.The angiogenic switch appears to be governed by the same geneticalterations that drive malignant conversion: the activation of oncogenesand the loss of tumour suppressor genes. Several growth factors act aspositive regulators of angiogenesis. Foremost among these are vascularendothelial growth factor (VEGF), basic fibroblast growth factor (bFGF),and angiogenin. Proteins such as thrombospondin (Tsp-1), angiostatin,and endostatin function as negative regulators of angiogenesis.

Inhibition of VEGFR2 but not VEGFR1 markedly disrupts angiogenicswitching, persistent angiogenesis, and initial tumor growth in a mousemodel. In late-stage tumors, phenotypic resistance to VEGFR2 blockadeemerged, as tumors regrew during treatment after an initial period ofgrowth suppression. This resistance to VEGF blockade involvesreactivation of tumour angiogenesis, independent of VEGF and associatedwith hypoxia-mediated induction of other proangiogenic factors,including members of the FGF family. These other proangiogenic signalsare functionally implicated in the revascularization and regrowth oftumours in the evasion phase, as FGF blockade impairs progression in theface of VEGF inhibition.

There is evidence for normalization of glioblastoma blood vessels inpatients treated with a pan-VEGF receptor tyrosine kinase inhibitor,AZD2171, in a phase 2 study. MRI determination of vessel normalizationin combination with circulating biomarkers provides for an effectivemeans to assess response to antiangiogenic agents.

PDGFR

A malignant tumour is the product of uncontrolled cell proliferation.Cell growth is controlled by a delicate balance between growth-promotingand growth-inhibiting factors. In normal tissue the production andactivity of these factors results in differentiated cells growing in acontrolled and regulated manner that maintains the normal integrity andfunctioning of the organ. The malignant cell has evaded this control;the natural balance is disturbed (via a variety of mechanisms) andunregulated, aberrant cell growth occurs. A growth factor of importancein tumour development is the platelet-derived growth factor (PDGF) thatcomprises a family of peptide growth factors that signal through cellsurface tyrosine kinase receptors (PDGFR) and stimulate various cellularfunctions including growth, proliferation, and differentiation.

Advantages of a Selective Inhibitor

Development of FGFR kinase inhibitors with a differentiated selectivityprofile provides a new opportunity to use these targeted agents inpatient sub-groups whose disease is driven by FGFR deregulation.Compounds that exhibit reduced inhibitory action on additional kinases,particularly VEGFR2 and PDGFR-beta, offer the opportunity to have adifferentiated side-effect or toxicity profile and as such allow for amore effective treatment of these indications. Inhibitors of VEGFR2 andPDGFR-beta are associated with toxicities such as hypertension or oedemarespectively. In the case of VEGFR2 inhibitors this hypertensive effectis often dose limiting, may be contraindicated in certain patientpopulations and requires clinical management.

Biological Activity and Therapeutic Uses

The compounds of the invention, and subgroups thereof, have fibroblastgrowth factor receptor (FGFR) inhibiting or modulating activity and/orvascular endothelial growth factor receptor (VEGFR) inhibiting ormodulating activity, and/or platelet derived growth factor receptor(PDGFR) inhibiting or modulating activity, and which will be useful inpreventing or treating disease states or conditions described herein. Inaddition the compounds of the invention, and subgroups thereof, will beuseful in preventing or treating diseases or condition mediated by thekinases. References to the preventing or prophylaxis or treatment of adisease state or condition such as cancer include within their scopealleviating or reducing the incidence of cancer.

As used herein, the term “modulation”, as applied to the activity of akinase, is intended to define a change in the level of biologicalactivity of the protein kinase. Thus, modulation encompassesphysiological changes which effect an increase or decrease in therelevant protein kinase activity. In the latter case, the modulation maybe described as “inhibition”. The modulation may arise directly orindirectly, and may be mediated by any mechanism and at anyphysiological level, including for example at the level of geneexpression (including for example transcription, translation and/orpost-translational modification), at the level of expression of genesencoding regulatory elements which act directly or indirectly on thelevels of kinase activity. Thus, modulation may implyelevated/suppressed expression or over- or under-expression of a kinase,including gene amplification (i.e. multiple gene copies) and/orincreased or decreased expression by a transcriptional effect, as wellas hyper-(or hypo-)activity and (de)activation of the protein kinase(s)(including (de)activation) by mutation(s). The terms “modulated”,“modulating” and “modulate” are to be interpreted accordingly.

As used herein, the term “mediated”, as used e.g. in conjunction with akinase as described herein (and applied for example to variousphysiological processes, diseases, states, conditions, therapies,treatments or interventions) is intended to operate limitatively so thatthe various processes, diseases, states, conditions, treatments andinterventions to which the term is applied are those in which the kinaseplays a biological role. In cases where the term is applied to adisease, state or condition, the biological role played by a kinase maybe direct or indirect and may be necessary and/or sufficient for themanifestation of the symptoms of the disease, state or condition (or itsaetiology or progression). Thus, kinase activity (and in particularaberrant levels of kinase activity, e.g. kinase over-expression) neednot necessarily be the proximal cause of the disease, state orcondition: rather, it is contemplated that the kinase mediated diseases,states or conditions include those having multifactorial aetiologies andcomplex progressions in which the kinase in question is only partiallyinvolved. In cases where the term is applied to treatment, prophylaxisor intervention, the role played by the kinase may be direct or indirectand may be necessary and/or sufficient for the operation of thetreatment, prophylaxis or outcome of the intervention. Thus, a diseasestate or condition mediated by a kinase includes the development ofresistance to any particular cancer drug or treatment.

Thus, for example, the compounds of the invention may be useful inalleviating or reducing the incidence of cancer.

More particularly, the compounds of the formulae (I) and sub-groupsthereof are inhibitors of FGFRs. For example, compounds of the inventionhave activity against FGFR1, FGFR2, FGFR3, and/or FGFR4, and inparticular FGFRs selected from FGFR1, FGFR2 and FGFR3; or in particularthe compounds of formula (I) and sub-groups thereof are inhibitors ofFGFR4.

Preferred compounds are compounds that inhibit one or more FGFR selectedfrom FGFR1, FGFR2, FGFR3, and FGFR4. Preferred compounds of theinvention are those having IC₅₀ values of less than 0.1 μM.

Compounds of the invention also have activity against VEGFR.

In addition many of the compounds of the invention exhibit selectivityfor the FGFR 1, 2, and/or 3, and/or 4 compared to VEGFR (in particularVEGFR2) and/or PDGFR and such compounds represent one preferredembodiment of the invention. In particular, the compounds exhibitselectivity over VEGFR2. For example, many compounds of the inventionhave IC₅₀ values against FGFR1, 2 and/or 3 and/or 4 that are between atenth and a hundredth of the IC₅₀ against VEGFR (in particular VEGFR2)and/or PDGFR B. In particular preferred compounds of the invention haveat least 10 times greater activity against or inhibition of FGFR inparticular FGFR1, FGFR2, FGFR3 and/or FGFR4 than VEGFR2. More preferablythe compounds of the invention have at least 100 times greater activityagainst or inhibition of FGFR in particular FGFR1, FGFR2, FGFR3 and/orFGFR4 than VEGFR2. This can be determined using the methods describedherein.

As a consequence of their activity in modulating or inhibiting FGFR,and/or VEGFR kinases, the compounds will be useful in providing a meansof preventing the growth or inducing apoptosis of neoplasias,particularly by inhibiting angiogenesis. It is therefore anticipatedthat the compounds will prove useful in treating or preventingproliferative disorders such as cancers. In addition, the compounds ofthe invention could be useful in the treatment of diseases in whichthere is a disorder of proliferation, apoptosis or differentiation.

In particular tumours with activating mutants of VEGFR or upregulationof VEGFR and patients with elevated levels of serum lactatedehydrogenase may be particularly sensitive to the compounds of theinvention. Patients with activating mutants of any of the isoforms ofthe specific RTKs discussed herein may also find treatment with thecompounds of the invention particularly beneficial. For example, VEGFRoverexpression in acute leukemia cells where the clonal progenitor mayexpress VEGFR. Also, particular tumours with activating mutants orupregulation or overexpression of any of the isoforms of FGFR such asFGFR1, FGFR2 or FGFR3 or FGFR4 may be particularly sensitive to thecompounds of the invention and thus patients as discussed herein withsuch particular tumours may also find treatment with the compounds ofthe invention particularly beneficial. It may be preferred that thetreatment is related to or directed at a mutated form of one of thereceptor tyrosine kinases, such as discussed herein. Diagnosis oftumours with such mutations could be performed using techniques known toa person skilled in the art and as described herein such as RTPCR andFISH.

Examples of cancers which may be treated (or inhibited) include, but arenot limited to, a carcinoma, for example a carcinoma of the bladder,breast, colon (e.g. colorectal carcinomas such as colon adenocarcinomaand colon adenoma), kidney, epidermis, liver, lung (for exampleadenocarcinoma, small cell lung cancer and non-small cell lungcarcinomas), oesophagus, head and neck, gall bladder, ovary, pancreas(e.g. exocrine pancreatic carcinoma), stomach, gastrointestinal (alsoknown as gastric) cancer (e.g. gastrointestinal stromal tumours),cervix, endometrium, thyroid, prostate, or skin (for example squamouscell carcinoma or dermatofibrosarcoma protuberans); a hematopoietictumour of lymphoid lineage, for example leukemia, acute lymphocyticleukemia, chronic lymphocytic leukemia, B-cell lymphoma (e.g. diffuselarge B-cell lymphoma), T-cell lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; ahematopoietic tumour of myeloid lineage, for example leukemias, acuteand chronic myelogenous leukemias, chronic myelomonocytic leukemia(CMML), myeloproliferative disorder, myeloproliferative syndrome,myelodysplastic syndrome, or promyelocytic leukemia; multiple myeloma;thyroid follicular cancer; a tumour of mesenchymal origin (e.g. Ewing'ssarcoma), for example fibrosarcoma or rhabdomyosarcoma; a tumour of thecentral or peripheral nervous system, for example astrocytoma,neuroblastoma, glioma (such as glioblastoma multiforme) or schwannoma;melanoma; seminoma; teratocarcinoma; osteosarcoma; xerodermapigmentosum; keratoctanthoma; thyroid follicular cancer; or Kaposi'ssarcoma.

Certain cancers are resistant to treatment with particular drugs. Thiscan be due to the type of the tumour or can arise due to treatment withthe compound. In this regard, references to multiple myeloma includesbortezomib sensitive multiple myeloma or refractory multiple myeloma.Similarly, references to chronic myelogenous leukemia includes imitanibsensitive chronic myelogenous leukemia and refractory chronicmyelogenous leukemia. Chronic myelogenous leukemia is also known aschronic myeloid leukemia, chronic granulocytic leukemia or CML.Likewise, acute myelogenous leukemia, is also called acute myeloblasticleukemia, acute granulocytic leukemia, acute nonlymphocytic leukaemia orAML.

The compounds of the invention can also be used in the treatment ofhematopoetic diseases of abnormal cell proliferation whetherpre-malignant or stable such as myeloproliferative diseases.Myeloproliferative diseases (“MPD”s) are a group of diseases of the bonemarrow in which excess cells are produced. They are related to, and mayevolve into, myelodysplastic syndrome. Myeloproliferative diseasesinclude polycythemia vera, essential thrombocythemia and primarymyelofibrosis. A further haematological disorder is hypereosinophilicsyndrome. T-cell lymphoproliferative diseases include those derived fromnatural Killer cells.

In addition the compounds of the invention can be used togastrointestinal (also known as gastric) cancer e.g. gastrointestinalstromal tumours. Gastrointestinal cancer refers to malignant conditionsof the gastrointestinal tract, including the esophagus, stomach, liver,biliary system, pancreas, bowels, and anus.

Thus, in the pharmaceutical compositions, uses or methods of thisinvention for treating a disease or condition comprising abnormal cellgrowth, the disease or condition comprising abnormal cell growth in oneembodiment is a cancer.

Particular subsets of cancers include multiple myeloma, bladder,cervical, prostate and thyroid carcinomas, lung, breast, and coloncancers.

A further subset of cancers includes multiple myeloma, bladder,hepatocellular, oral squamous cell carcinoma and cervical carcinomas.

The compound of the invention, having FGFR such as FGFR1 inhibitoryactivity, may be particularly useful in the treatment or prevention ofbreast cancer in particular Classic Lobular Carcinomas (CLC).

As the compounds of the invention have FGFR4 activity they will also beuseful in the treatment of prostate or pituitary cancers, or they willbe useful in the treatment of breast cancer, lung cancer, prostatecancer, liver cancer (HCC) or lung cancer.

In particular the compounds of the invention as FGFR inhibitors, areuseful in the treatment of multiple myeloma, myeloproliferatoivedisorders, endometrial cancer, prostate cancer, bladder cancer, lungcancer, ovarian cancer, breast cancer, gastric cancer, colorectalcancer, and oral squamous cell carcinoma.

Further subsets of cancer are multiple myeloma, endometrial cancer,bladder cancer, cervical cancer, prostate cancer, lung cancer, breastcancer, colorectal cancer and thyroid carcinomas.

In particular the compounds of the invention are useful in the treatmentof multiple myeloma (in particular multiple myeloma with t(4;14)translocation or overexpressing FGFR3), prostate cancer (hormonerefractory prostrate carcinomas), endometrial cancer (in particularendometrial tumours with activating mutations in FGFR2) and breastcancer (in particular lobular breast cancer).

In particular the compounds are useful in the treatment of lobularcarcinomas such as CLC (Classic lobular carcinoma).

As the compounds have activity against FGFR3 they will be useful in thetreatment of multiple myeloma and bladder cancer.

In particular the compounds are useful for the treatment of t(4;14)translocation positive multiple myeloma.

In one embodiment the compounds may be useful for the treatment ofsarcoma. In one embodiment the compounds may be useful for the treatmentof lung cancer, e.g. squamous cell carcinoma.

As the compounds have activity against FGFR2 they will be useful in thetreatment of endometrial, ovarian, gastric and colorectal cancers. FGFR2is also overexpressed in epithelial ovarian cancer, therefore thecompounds of the invention may be specifically useful in treatingovarian cancer such as epithelial ovarian cancer.

In one embodiment, the compounds may be useful for the treatment of lungcancer, in particular NSCLC, squamous cell carcinoma, liver cancer,kidney cancer, breast cancer, colon cancer, colorectal cancer, prostatecancer.

Compounds of the invention may also be useful in the treatment oftumours pre-treated with VEGFR2 inhibitor or VEGFR2 antibody (e.g.Avastin).

In particular the compounds of the invention may be useful in thetreatment of VEGFR2-resistant tumours. VEGFR2 inhibitors and antibodiesare used in the treatment of thyroid and renal cell carcinomas,therefore the compounds of the invention may be useful in the treatmentof VEGFR2-resistant thyroid and renal cell carcinomas.

The cancers may be cancers which are sensitive to inhibition of any oneor more FGFRs selected from FGFR1, FGFR2, FGFR3, FGFR4, for example, oneor more FGFRs selected from FGFR1, FGFR2 or FGFR3.

Whether or not a particular cancer is one which is sensitive toinhibition of FGFR or VEGFR signalling may be determined by means of acell growth assay as set out below or by a method as set out in thesection headed “Methods of Diagnosis”.

The compounds of the invention, and in particular those compounds havingFGFR, or VEGFR inhibitory activity, may be particularly useful in thetreatment or prevention of cancers of a type associated with orcharacterised by the presence of elevated levels of FGFR, or VEGFR, forexample the cancers referred to in this context in the introductorysection of this application.

The compounds of the present invention may be useful for the treatmentof the adult population. The compounds of the present invention may beuseful for the treatment of the pediatric population.

It has been discovered that some FGFR inhibitors can be used incombination with other anticancer agents. For example, it may bebeneficial to combine an inhibitor that induces apoptosis with anotheragent which acts via a different mechanism to regulate cell growth thustreating two of the characteristic features of cancer development.Examples of such combinations are set out below.

The compounds of the invention may be useful in treating otherconditions which result from disorders in proliferation such as type IIor non-insulin dependent diabetes mellitus, autoimmune diseases, headtrauma, stroke, epilepsy, neurodegenerative diseases such asAlzheimer's, motor neurone disease, progressive supranuclear palsy,corticobasal degeneration and Pick's disease for example autoimmunediseases and neurodegenerative diseases.

One sub-group of disease states and conditions that the compounds of theinvention may be useful consists of inflammatory diseases,cardiovascular diseases and wound healing.

FGFR, and VEGFR are also known to play a role in apoptosis,angiogenesis, proliferation, differentiation and transcription andtherefore the compounds of the invention could also be useful in thetreatment of the following diseases other than cancer; chronicinflammatory diseases, for example systemic lupus erythematosus,autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis,inflammatory bowel disease, autoimmune diabetes mellitus, Eczemahypersensitivity reactions, asthma, COPD, rhinitis, and upperrespiratory tract disease; cardiovascular diseases for example cardiachypertrophy, restenosis, atherosclerosis; neurodegenerative disorders,for example Alzheimer's disease, AIDS-related dementia, Parkinson'sdisease, amyotropic lateral sclerosis, retinitis pigmentosa, spinalmuscular atropy and cerebellar degeneration; glomerulonephritis;myelodysplastic syndromes, ischemic injury associated myocardialinfarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis,toxin-induced or alcohol related liver diseases, haematologicaldiseases, for example, chronic anemia and aplastic anemia; degenerativediseases of the musculoskeletal system, for example, osteoporosis andarthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiplesclerosis, kidney diseases and cancer pain.

In addition, mutations of FGFR2 are associated with several severeabnormalities in human skeletal development and thus the compounds ofinvention could be useful in the treatment of abnormalities in humanskeletal development, including abnormal ossification of cranial sutures(craniosynostosis), Apert (AP) syndrome, Crouzon syndrome, Jackson-Weisssyndrome, Beare-Stevenson cutis gyrate syndrome, and Pfeiffer syndrome.

The compound of the invention, having FGFR such as FGFR2 or FGFR3inhibitory activity, may be particularly useful in the treatment orprevention of the skeletal diseases. Particular skeletal diseases areachondroplasia or thanatophoric dwarfism (also known as thanatophoricdysplasia).

The compound of the invention, having FGFR such as FGFR1, FGFR2 or FGFR3inhibitory activity, may be particularly useful in the treatment orprevention in pathologies in which progressive fibrosis is a symptom.Fibrotic conditions in which the compounds of the inventions may beuseful in the treatment of include diseases exhibiting abnormal orexcessive deposition of fibrous tissue for example in liver cirrhosis,glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoidarthritis, as well as the natural process of wound healing. Inparticular the compounds of the inventions may also be useful in thetreatment of lung fibrosis in particular in idiopathic pulmonaryfibrosis.

The over-expression and activation of FGFR and VEGFR in tumor-associatedvasculature has also suggested a role for compounds of the invention inpreventing and disrupting initiation of tumor angiogenesis. Inparticular the compounds of the invention may be useful in the treatmentof cancer, metastasis, leukemia's such as CLL, ocular diseases such asage-related macular degeneration in particular wet form of age-relatedmacular degeneration, ischemic proliferative retinopathies such asretinopathy of prematurity (ROP) and diabetic retinopathy, rheumatoidarthritis and hemangioma.

The activity of the compounds of the invention as inhibitors of FGFR1-4,VEGFR and/or PDGFR A/B can be measured using the assays set forth in theexamples below and the level of activity exhibited by a given compoundcan be defined in terms of the IC₅₀ value. Preferred compounds of thepresent invention are compounds having an IC₅₀ value of less than 1 μM,more preferably less than 0.1 μM.

The invention provides compounds that have FGFR inhibiting or modulatingactivity, and which may be useful in preventing or treating diseasestates or conditions mediated by FGFR kinases.

In one embodiment, there is provided a compound as defined herein foruse in therapy, for use as a medicine. In a further embodiment, there isprovided a compound as defined herein for use in the prophylaxis ortreatment, in particular in the treatment, of a disease state orcondition mediated by a FGFR kinase.

Thus, for example, the compounds of the invention may be useful inalleviating or reducing the incidence of cancer. Therefore, in a furtherembodiment, there is provided a compound as defined herein for use inthe prophylaxis or treatment, in particular the treatment, of cancer. Inone embodiment, the compound as defined herein is for use in theprophylaxis or treatment of FGFR-dependent cancer. In one embodiment,the compound as defined herein is for use in the prophylaxis ortreatment of cancer mediated by FGFR kinases.

Accordingly, the invention provides inter alia:

-   -   A method for the prophylaxis or treatment of a disease state or        condition mediated by a FGFR kinase, which method comprises        administering to a subject in need thereof a compound of the        formula (I) as defined herein.    -   A method for the prophylaxis or treatment of a disease state or        condition as described herein, which method comprises        administering to a subject in need thereof a compound of the        formula (I) as defined herein.    -   A method for the prophylaxis or treatment of cancer, which        method comprises administering to a subject in need thereof a        compound of the formula (I) as defined herein.    -   A method for alleviating or reducing the incidence of a disease        state or condition mediated by a FGFR kinase, which method        comprises administering to a subject in need thereof a compound        of the formula (I) as defined herein.    -   A method of inhibiting a FGFR kinase, which method comprises        contacting the kinase with a kinase-inhibiting compound of the        formula (I) as defined herein.    -   A method of modulating a cellular process (for example cell        division) by inhibiting the activity of a FGFR kinase using a        compound of the formula (I) as defined herein.    -   A compound of formula (I) as defined herein for use as a        modulator of a cellular process (for example cell division) by        inhibiting the activity of a FGFR kinase.    -   A compound of formula (I) as defined herein for use in the        prophylaxis or treatment of cancer, in particular the treatment        of cancer.    -   A compound of formula (I) as defined herein for use as a        modulator (e.g. inhibitor) of FGFR.    -   The use of a compound of formula (I) as defined herein for the        manufacture of a medicament for the prophylaxis or treatment of        a disease state or condition mediated by a FGFR kinase, the        compound having the formula (I) as defined herein.    -   The use of a compound of formula (I) as defined herein for the        manufacture of a medicament for the prophylaxis or treatment of        a disease state or condition as described herein.    -   The use of a compound of formula (I) as defined herein for the        manufacture of a medicament for the prophylaxis or treatment, in        particular the treatment, of cancer.    -   The use of a compound of formula (I) as defined herein for the        manufacture of a medicament for modulating (e.g. inhibiting) the        activity of FGFR.    -   Use of a compound of formula (I) as defined herein in the        manufacture of a medicament for modulating a cellular process        (for example cell division) by inhibiting the activity of a FGFR        kinase.    -   The use of a compound of the formula (I) as defined herein for        the manufacture of a medicament for prophylaxis or treatment of        a disease or condition characterised by up-regulation of a FGFR        kinase (e.g. FGFR1 or FGFR2 or FGFR3 or FGFR4).    -   The use of a compound of the formula (I) as defined herein for        the manufacture of a medicament for the prophylaxis or treatment        of a cancer, the cancer being one which is characterised by        up-regulation of a FGFR kinase (e.g. FGFR1 or FGFR2 or FGFR3 or        FGFR4).    -   The use of a compound of the formula (I) as defined herein for        the manufacture of a medicament for the prophylaxis or treatment        of cancer in a patient selected from a sub-population possessing        a genetic aberrations of FGFR3 kinase.    -   The use of a compound of the formula (I) as defined herein for        the manufacture of a medicament for the prophylaxis or treatment        of cancer in a patient who has been diagnosed as forming part of        a sub-population possessing a genetic aberrations of FGFR3        kinase.    -   A method for the prophylaxis or treatment of a disease or        condition characterised by up-regulation of a FGFR kinase (e.g.        FGFR1 or FGFR2 or FGFR3 or FGFR4), the method comprising        administering a compound of the formula (I) as defined herein.    -   A method for alleviating or reducing the incidence of a disease        or condition characterised by up-regulation of a FGFR kinase        (e.g. FGFR1 or FGFR2 or FGFR3 or FGFR4), the method comprising        administering a compound of the formula (I) as defined herein.    -   A method for the prophylaxis or treatment of (or alleviating or        reducing the incidence of) cancer in a patient suffering from or        suspected of suffering from cancer; which method comprises (i)        subjecting a patient to a diagnostic test to determine whether        the patient possesses a genetic aberrations of FGFR3 gene;        and (ii) where the patient does possess the said variant,        thereafter administering to the patient a compound of the        formula (I) as defined herein having FGFR3 kinase inhibiting        activity.    -   A method for the prophylaxis or treatment of (or alleviating or        reducing the incidence of) a disease state or condition        characterised by up-regulation of an FGFR kinase (e.g. FGFR1 or        FGFR2 or FGFR3 or FGFR4); which method comprises (i) subjecting        a patient to a diagnostic test to detect a marker characteristic        of up-regulation of a FGFR kinase (e.g. FGFR1 or FGFR2 or FGFR3        or FGFR4) and (ii) where the diagnostic test is indicative of        up-regulation of a FGFR kinase, thereafter administering to the        patient a compound of the formula (I) as defined herein having        FGFR kinase inhibiting activity.

In one embodiment, the disease mediated by FGFR kinases is a oncologyrelated disease (e.g. cancer). In one embodiment, the disease mediatedby FGFR kinases is a non-oncology related disease (e.g. any diseasedisclosed herein excluding cancer). In one embodiment the diseasemediated by FGFR kinases is a condition described herein. In oneembodiment the disease mediated by FGFR kinases is a skeletal conditiondescribed herein. Particular abnormalities in human skeletaldevelopment, include abnormal ossification of cranial sutures(craniosynostosis), Apert (AP) syndrome, Crouzon syndrome, Jackson-Weisssyndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome,achondroplasia and thanatophoric dwarfism (also known as thanatophoricdysplasia).

Mutated Kinases

Drug resistant kinase mutations can arise in patient populations treatedwith kinase inhibitors. These occur, in part, in the regions of theprotein that bind to or interact with the particular inhibitor used intherapy. Such mutations reduce or increase the capacity of the inhibitorto bind to and inhibit the kinase in question. This can occur at any ofthe amino acid residues which interact with the inhibitor or areimportant for supporting the binding of said inhibitor to the target. Aninhibitor that binds to a target kinase without requiring theinteraction with the mutated amino acid residue will likely beunaffected by the mutation and will remain an effective inhibitor of theenzyme.

A study in gastric cancer patient samples showed the presence of twomutations in FGFR2, Ser167Pro in exon 111a and a splice site mutation940-2A-G in exon IllIc. These mutations are identical to the germlineactivating mutations that cause craniosynotosis syndromes and wereobserved in 13% of primary gastric cancer tissues studied. In additionactivating mutations in FGFR3 were observed in 5% of the patient samplestested and overexpression of FGFRs has been correlated with a poorprognosis in this patient group.

In addition there are chromosomal translocations or point mutations thathave been observed in FGFR which give rise to gain-of-function,over-expressed, or constitutively active biological states.

The compounds of the invention would therefore find particularapplication in relation to cancers which express a mutated moleculartarget such as FGFR. Diagnosis of tumours with such mutations could beperformed using techniques known to a person skilled in the art and asdescribed herein such as RTPCR and FISH.

It has been suggested that mutations of a conserved threonine residue atthe ATP binding site of FGFR would result in inhibitor resistance. Theamino acid valine 561 has been mutated to a methionine in FGFR1 whichcorresponds to previously reported mutations found in Abl (T315) andEGFR (T766) that have been shown to confer resistance to selectiveinhibitors. Assay data for FGFR1V561M showed that this mutationconferred resistance to a tyrosine kinase inhibitor compared to that ofthe wild type.

Methods of Diagnosis

Prior to administration of a compound of the formula (I), a patient maybe screened to determine whether a disease or condition from which thepatient is or may be suffering is one which would be susceptible totreatment with a compound having activity against FGFR, and/or VEGFR.

For example, a biological sample taken from a patient may be analysed todetermine whether a condition or disease, such as cancer, that thepatient is or may be suffering from is one which is characterised by agenetic abnormality or abnormal protein expression which leads toup-regulation of the levels or activity of FGFR, and/or VEGFR or tosensitisation of a pathway to normal FGFR, and/or VEGFR activity, or toupregulation of these growth factor signalling pathways such as growthfactor ligand levels or growth factor ligand activity or to upregulationof a biochemical pathway downstream of FGFR, and/or VEGFR activation.

Examples of such abnormalities that result in activation orsensitisation of the FGFR, and/or VEGFR signal include loss of, orinhibition of apoptotic pathways, up-regulation of the receptors orligands, or presence of mutant variants of the receptors or ligands e.gPTK variants. Tumours with mutants of FGFR1, FGFR2 or FGFR3 or FGFR4 orup-regulation, in particular over-expression of FGFR1, orgain-of-function mutants of FGFR2 or FGFR3 may be particularly sensitiveto FGFR inhibitors.

For example, point mutations engendering gain-of-function in FGFR2 havebeen identified in a number of conditions. In particular activatingmutations in FGFR2 have been identified in 10% of endometrial tumours.

In addition, genetic aberrations of the FGFR3 receptor tyrosine kinasesuch as chromosomal translocations or point mutations resulting inectopically expressed or deregulated, constitutively active, FGFR3receptors have been identified and are linked to a subset of multiplemyelomas, bladder and cervical carcinomas. A particular mutation T6741of the PDGF receptor has been identified in imatinib-treated patients.In addition, a gene amplification of 8p12-p11.2 was demonstrated in −50%of lobular breast cancer (CLC) cases and this was shown to be linkedwith an increased expression of FGFR1. Preliminary studies with siRNAdirected against FGFR1, or a small molecule inhibitor of the receptor,showed cell lines harbouring this amplification to be particularlysensitive to inhibition of this signalling pathway.

Alternatively, a biological sample taken from a patient may be analysedfor loss of a negative regulator or suppressor of FGFR or VEGFR. In thepresent context, the term “loss” embraces the deletion of a geneencoding the regulator or suppressor, the truncation of the gene (forexample by mutation), the truncation of the transcribed product of thegene, or the inactivation of the transcribed product (e.g. by pointmutation) or sequestration by another gene product.

The term up-regulation includes elevated expression or over-expression,including gene amplification (i.e. multiple gene copies) and increasedexpression by a transcriptional effect, and hyperactivity andactivation, including activation by mutations. Thus, the patient may besubjected to a diagnostic test to detect a marker characteristic ofup-regulation of FGFR, and/or VEGFR. The term diagnosis includesscreening. By marker we include genetic markers including, for example,the measurement of DNA composition to identify mutations of FGFR, and/orVEGFR. The term marker also includes markers which are characteristic ofup regulation of FGFR and/or VEGFR, including enzyme activity, enzymelevels, enzyme state (e.g. phosphorylated or not) and mRNA levels of theaforementioned proteins.

The diagnostic tests and screens are typically conducted on a biologicalsample selected from tumour biopsy samples, blood samples (isolation andenrichment of shed tumour cells), stool biopsies, sputum, chromosomeanalysis, pleural fluid, peritoneal fluid, buccal spears, biopsy orurine.

Methods of identification and analysis of mutations and up-regulation ofproteins are known to a person skilled in the art. Screening methodscould include, but are not limited to, standard methods such asreverse-transcriptase polymerase chain reaction (RT-PCR) or in-situhybridization such as fluorescence in situ hybridization (FISH).

Identification of an individual carrying a mutation in FGFR, and/orVEGFR may mean that the patient would be particularly suitable fortreatment with a FGFR, and/or VEGFR inhibitor. Tumours maypreferentially be screened for presence of a FGFR, and/or VEGFR variantprior to treatment. The screening process will typically involve directsequencing, oligonucleotide microarray analysis, or a mutant specificantibody. In addition, diagnosis of tumours with such mutations could beperformed using techniques known to a person skilled in the art and asdescribed herein such as RT-PCR and FISH.

In addition, mutant forms of, for example FGFR or VEGFR2, can beidentified by direct sequencing of, for example, tumour biopsies usingPCR and methods to sequence PCR products directly as hereinbeforedescribed. The skilled artisan will recognize that all such well-knowntechniques for detection of the over expression, activation or mutationsof the aforementioned proteins could be applicable in the present case.

In screening by RT-PCR, the level of mRNA in the tumour is assessed bycreating a cDNA copy of the mRNA followed by amplification of the cDNAby PCR. Methods of PCR amplification, the selection of primers, andconditions for amplification, are known to a person skilled in the art.Nucleic acid manipulations and PCR are carried out by standard methods,as described for example in Ausubel, F. M. et al., eds. (2004) CurrentProtocols in Molecular Biology, John Wiley & Sons Inc., or Innis, M. A.et al., eds. (1990) PCR Protocols: a guide to methods and applications,Academic Press, San Diego. Reactions and manipulations involving nucleicacid techniques are also described in Sambrook et al., (2001), 3^(rd)Ed, Molecular Cloning: A Laboratory Manual, Cold Spring HarborLaboratory Press. Alternatively a commercially available kit for RT-PCR(for example Roche Molecular Biochemicals) may be used, or methodologyas set forth in U.S. Pat. Nos. 4,666,828; 4,683,202; 4,801,531;5,192,659, 5,272,057, 5,882,864, and 6,218,529 and incorporated hereinby reference. An example of an in-situ hybridisation technique forassessing mRNA expression would be fluorescence in-situ hybridisation(FISH) (see Angerer (1987) Meth. Enzymol., 152: 649).

Generally, in situ hybridization comprises the following major steps:(1) fixation of tissue to be analyzed; (2) prehybridization treatment ofthe sample to increase accessibility of target nucleic acid, and toreduce nonspecific binding; (3) hybridization of the mixture of nucleicacids to the nucleic acid in the biological structure or tissue; (4)post-hybridization washes to remove nucleic acid fragments not bound inthe hybridization, and (5) detection of the hybridized nucleic acidfragments. The probes used in such applications are typically labelled,for example, with radioisotopes or fluorescent reporters. Preferredprobes are sufficiently long, for example, from about 50, 100, or 200nucleotides to about 1000 or more nucleotides, to enable specifichybridization with the target nucleic acid(s) under stringentconditions. Standard methods for carrying out FISH are described inAusubel, F. M. et al., eds. (2004) Current Protocols in MolecularBiology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization:Technical Overview by John M. S. Bartlett in Molecular Diagnosis ofCancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004,pps. 077-088; Series: Methods in Molecular Medicine.

Methods for gene expression profiling are described by (DePrimo et al.(2003), BMC Cancer, 3:3). Briefly, the protocol is as follows:double-stranded cDNA is synthesized from total RNA Using a (dT)24oligomer for priming first-strand cDNA synthesis, followed by secondstrand cDNA synthesis with random hexamer primers. The double-strandedcDNA is used as a template for in vitro transcription of cRNA usingbiotinylated ribonucleotides. cRNA is chemically fragmented according toprotocols described by Affymetrix (Santa Clara, Calif., USA), and thenhybridized overnight on Human Genome Arrays.

Alternatively, the protein products expressed from the mRNAs may beassayed by immunohistochemistry of tumour samples, solid phaseimmunoassay with microtitre plates, Western blotting, 2-dimensionalSDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and othermethods known in the art for detection of specific proteins. Detectionmethods would include the use of site specific antibodies. The skilledperson will recognize that all such well-known techniques for detectionof upregulation of FGFR, and/or VEGFR, or detection of FGFR, and/orVEGFR variants or mutants could be applicable in the present case.

Abnormal levels of proteins such as FGFR or VEGFR can be measured usingstandard enzyme assays, for example, those assays described herein.Activation or overexpression could also be detected in a tissue sample,for example, a tumour tissue. By measuring the tyrosine kinase activitywith an assay such as that from Chemicon International. The tyrosinekinase of interest would be immunoprecipitated from the sample lysateand its activity measured.

Alternative methods for the measurement of the over expression oractivation of FGFR or VEGFR including the isoforms thereof, include themeasurement of microvessel density. This can for example be measuredusing methods described by Orre and Rogers (Int J Cancer (1999), 84(2)101-8). Assay methods also include the use of markers, for example, inthe case of VEGFR these include CD31, CD34 and CD105.

Therefore all of these techniques could also be used to identify tumoursparticularly suitable for treatment with the compounds of the invention.

The compounds of the invention are particular useful in treatment of apatient having a mutated FGFR. The G697C mutation in FGFR3 is observedin 62% of oral squamous cell carcmonas and causes constitutiveactivation of the kinase activity. Activating mutations of FGFR3 havealso been identified in bladder carcinoma cases. These mutations were of6 kinds with varying degrees of prevelence: R248C, S249C, G372C, S373C,Y375C, K₆₅₂Q. In addition, a Gly388Arg polymorphism in FGFR4 has beenfound to be associated with increased incidence and aggressiveness ofprostate, colon, lung, liver (HCC) and breast cancer.

Therefore in a further aspect the invention includes use of a compoundaccording to the invention for the manufacture of a medicament for thetreatment or prophylaxis of a disease state or condition in a patientwho has been screened and has been determined as suffering from, orbeing at risk of suffering from, a disease or condition which would besusceptible to treatment with a compound having activity against FGFR.

Particular mutations a patient is screened for include G697C, R248C,S249C, G372C, S373C, Y375C, K652Q mutations in FGFR3 and Gly388Argpolymorphism in FGFR4.

In another aspect the invention includes a compound of the invention foruse in the prophylaxis or treatment of cancer in a patient selected froma sub-population possessing a variant of the FGFR gene (for exampleG697C mutation in FGFR3 and Gly388Arg polymorphism in FGFR4).

MRI determination of vessel normalization (e.g. using MRI gradient echo,spin echo, and contrast enhancement to measure blood volume, relativevessel size, and vascular permeability) in combination with circulatingbiomarkers (circulating progenitor cells (CPCs), CECs, SDF1, and FGF2)may also be used to identify VEGFR2-resistant tumours for treatment witha compound of the invention.

Pharmaceutical Compositions and Combinations

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes.

In one embodiment the pharmaceutical composition (e.g. formulation)comprises at least one active compound of the invention together withone or more pharmaceutically acceptable carriers, adjuvants, excipients,diluents, fillers, buffers, stabilisers, preservatives, lubricants, orother materials well known to those skilled in the art and optionallyother therapeutic or prophylactic agents.

To prepare the pharmaceutical compositions of this invention, aneffective amount of a compound of the present invention, as the activeingredient is combined in intimate admixture with a pharmaceuticallyacceptable carrier, which carrier may take a wide variety of formsdepending on the form of preparation desired for administration. Thepharmaceutical compositions can be in any form suitable for oral,parenteral, topical, intranasal, ophthalmic, otic, rectal,intra-vaginal, or transdermal administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for administration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols and the like in the case oforal liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets.

Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are obviously employed. For parenteralcompositions, the carrier will usually comprise sterile water, at leastin large part, though other ingredients, to aid solubility for example,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable suspensions may alsobe prepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wetting agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not cause a significant deleterious effect to theskin. Said additives may facilitate the administration to the skinand/or may be helpful for preparing the desired compositions. Thesecompositions may be administered in various ways, e.g., as a transdermalpatch, as a spot-on, as an ointment. It is especially advantageous toformulate the aforementioned pharmaceutical compositions in dosage unitform for ease of administration and uniformity of dosage. Dosage unitform as used in the specification and claims herein refers to physicallydiscrete units suitable as unitary dosages, each unit containing apredetermined quantity of active ingredient calculated to produce thedesired therapeutic effect in association with the requiredpharmaceutical carrier. Examples of such dosage unit forms are tablets(including scored or coated tablets), capsules, pills, powder packets,wafers, injectable solutions or suspensions, teaspoonfuls,tablespoonfuls and the like, and segregated multiples thereof.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient, calculated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The compound of the invention is administered in an amount sufficient toexert its anti-tumour activity.

Those skilled in the art could easily determine the effective amountfrom the test results presented hereinafter. In general it iscontemplated that a therapeutically effective amount would be from 0.005mg/kg to 100 mg/kg body weight, and in particular from 0.005 mg/kg to 10mg/kg body weight. It may be appropriate to administer the required doseas single, two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 0.5 to 500 mg, in particular 1 mg to 500mg, more in particular 10 mg to 500 mg of active ingredient per unitdosage form.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% by weight, more preferablyfrom 0.1 to 70% by weight, even more preferably from 0.1 to 50% byweight of the compound of the present invention, and, from 1 to 99.95%by weight, more preferably from 30 to 99.9% by weight, even morepreferably from 50 to 99.9% by weight of a pharmaceutically

acceptable carrier, all percentages being based on the total weight ofthe composition.

As another aspect of the present invention, a combination of a compoundof the present invention with another anticancer agent is envisaged,especially for use as a medicine, more specifically for use in thetreatment of cancer or related diseases.

For the treatment of the above conditions, the compounds of theinvention may be advantageously employed in combination with one or moreother medicinal agents, more particularly, with other anti-cancer agentsor adjuvants in cancer therapy. Examples of anti-cancer agents oradjuvants (supporting agents in the therapy) include but are not limitedto:

-   -   platinum coordination compounds for example cisplatin optionally        combined with amifostine, carboplatin or oxaliplatin;    -   taxane compounds for example paclitaxel, paclitaxel protein        bound particles (Abraxane™) or docetaxel;    -   topoisomerase I inhibitors such as camptothecin compounds for        example irinotecan, SN-38, topotecan, topotecan hcl;    -   topoisomerase II inhibitors such as anti-tumour        epipodophyllotoxins or podophyllotoxin derivatives for example        etoposide, etoposide phosphate or teniposide;    -   anti-tumour vinca alkaloids for example vinblastine, vincristine        or vinorelbine;    -   anti-tumour nucleoside derivatives for example 5-fluorouracil,        leucovorin, gemcitabine, gemcitabine hcl, capecitabine,        cladribine, fludarabine, nelarabine;    -   alkylating agents such as nitrogen mustard or nitrosourea for        example cyclophosphamide, chlorambucil, carmustine, thiotepa,        mephalan (melphalan), lomustine, altretamine, busulfan,        dacarbazine, estramustine, ifosfamide optionally in combination        with mesna, pipobroman, procarbazine, streptozocin,        telozolomide, uracil;    -   anti-tumour anthracycline derivatives for example daunorubicin,        doxorubicin optionally in combination with dexrazoxane, doxil,        idarubicin, mitoxantrone, epirubicin, epirubicin hcl,        valrubicin;    -   molecules that target the IGF-1 receptor for example        picropodophilin;    -   tetracarcin derivatives for example tetrocarcin A;    -   glucocorticoiden for example prednisone;    -   antibodies for example trastuzumab (HER2 antibody), rituximab        (CD₂O antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab,        pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab        tiuxetan, nofetumomab, panitumumab, tositumomab, CNTO 328;    -   estrogen receptor antagonists or selective estrogen receptor        modulators or inhibitors of estrogen synthesis for example        tamoxifen, fulvestrant, toremifene, droloxifene, faslodex,        raloxifene or letrozole;    -   aromatase inhibitors such as exemestane, anastrozole, letrazole,        testolactone and vorozole;    -   differentiating agents such as retinoids, vitamin D or retinoic        acid and retinoic acid metabolism blocking agents (RAMBA) for        example accutane;    -   DNA methyl transferase inhibitors for example azacytidine or        decitabine;    -   antifolates for example premetrexed disodium;    -   antibiotics for example antinomycin D, bleomycin, mitomycin C,        dactinomycin, caminomycin, daunomycin, levamisole, plicamycin,        mithramycin;    -   antimetabolites for example clofarabine, aminopterin, cytosine        arabinoside or methotrexate, azacitidine, cytarabine,        floxuridine, pentostatin, thioguanine;    -   apoptosis inducing agents and antiangiogenic agents such as        Bcl-2 inhibitors for example YC 137, BH 312, ABT 737, gossypol,        HA 14-1, TW 37 or decanoic acid;    -   tubuline-binding agents for example combrestatin, colchicines or        nocodazole;    -   kinase inhibitors (e.g. EGFR (epithelial growth factor receptor)        inhibitors, MTKI (multi target kinase inhibitors), mTOR        inhibitors) for example flavoperidol, imatinib mesylate,        erlotinib, gefitinib, dasatinib, lapatinib, lapatinib        ditosylate, sorafenib, sunitinib, sunitinib maleate,        temsirolimus;    -   farnesyltransferase inhibitors for example tipifarnib;    -   histone deacetylase (HDAC) inhibitors for example sodium        butyrate, suberoylanilide hydroxamide acid (SAHA), depsipeptide        (FR 901228), NVP-LAQ824, R306465, JNJ-26481585, trichostatin A,        vorinostat;    -   Inhibitors of the ubiquitin-proteasome pathway for example        PS-341, MLN 0.41 or bortezomib;    -   Yondelis;    -   Telomerase inhibitors for example telomestatin;    -   Matrix metalloproteinase inhibitors for example batimastat,        marimastat, prinostat or metastat.    -   Recombinant interleukins for example aldesleukin, denileukin        diftitox, interferon alfa 2a, interferon alfa 2b, peginterferon        alfa 2b    -   MAPK inhibitors    -   Retinoids for example alitretinoin, bexarotene, tretinoin    -   Arsenic trioxide    -   Asparaginase    -   Steroids for example dromostanolone propionate, megestrol        acetate, nandrolone (decanoate, phenpropionate), dexamethasone    -   Gonadotropin releasing hormone agonists or antagonists for        example abarelix, goserelin acetate, histrelin acetate,        leuprolide acetate    -   Thalidomide, lenalidomide    -   Mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase,        rasburicase    -   BH3 mimetics for example ABT-737    -   MEK inhibitors for example PD98059, AZD6244, CI-1040    -   colony-stimulating factor analogs for example filgrastim,        pegfilgrastim, sargramostim; erythropoietin or analogues thereof        (e.g. darbepoetin alfa); interleukin 11; oprelvekin;        zoledronate, zoledronic acid; fentanyl; bisphosphonate;        palifermin.    -   a steroidal cytochrome P450 17 alpha-hydroxylase-17,20-lyase        inhibitor (CYP17), e.g. abiraterone, abiraterone acetate.

The compounds of the present invention also have therapeuticapplications in sensitising tumour cells for radiotherapy andchemotherapy.

Hence the compounds of the present invention can be used as“radiosensitizer” and/or “chemosensitizer” or can be given incombination with another “radiosensitizer” and/or “chemosensitizer”.

The term “radiosensitizer”, as used herein, is defined as a molecule,preferably a low molecular weight molecule, administered to animals intherapeutically effective amounts to increase the sensitivity of thecells to ionizing radiation and/or to promote the treatment of diseaseswhich are treatable with ionizing radiation.

The term “chemosensitizer”, as used herein, is defined as a molecule,preferably a low molecular weight molecule, administered to animals intherapeutically effective amounts to increase the sensitivity of cellsto chemotherapy and/or promote the treatment of diseases which aretreatable with chemotherapeutics.

Several mechanisms for the mode of action of radiosensitizers have beensuggested in the literature including: hypoxic cell radiosensitizers(e.g., 2-nitroimidazole compounds, and benzotriazine dioxide compounds)mimicking oxygen or alternatively behave like bioreductive agents underhypoxia; non-hypoxic cell radiosensitizers (e.g., halogenatedpyrimidines) can be analogoues of DNA bases and preferentiallyincorporate into the DNA of cancer cells and thereby promote theradiation-induced breaking of DNA molecules and/or prevent the normalDNA repair mechanisms; and various other potential mechanisms of actionhave been hypothesized for radiosensitizers in the treatment of disease.

Many cancer treatment protocols currently employ radiosensitizers inconjunction with radiation of x-rays. Examples of x-ray activatedradiosensitizers include, but are not limited to, the following:metronidazole, misonidazole, desmethylmisonidazole, pimonidazole,etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145,nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR),bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin,and therapeutically effective analogs and derivatives of the same.

Photodynamic therapy (PDT) of cancers employs visible light as theradiation activator of the sensitizing agent. Examples of photodynamicradiosensitizers include the following, but are not limited to:hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, tinetioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines,phthalocyanines, zinc phthalocyanine, and therapeutically effectiveanalogs and derivatives of the same.

Radiosensitizers may be administered in conjunction with atherapeutically effective amount of one or more other compounds,including but not limited to: compounds which promote the incorporationof radiosensitizers to the target cells; compounds which control theflow of therapeutics, nutrients, and/or oxygen to the target cells;chemotherapeutic agents which act on the tumour with or withoutadditional radiation; or other therapeutically effective compounds fortreating cancer or other diseases.

Chemosensitizers may be administered in conjunction with atherapeutically effective amount of one or more other compounds,including but not limited to: compounds which promote the incorporationof chemosensitizers to the target cells; compounds which control theflow of therapeutics, nutrients, and/or oxygen to the target cells;chemotherapeutic agents which act on the tumour or other therapeuticallyeffective compounds for treating cancer or other disease. Calciumantagonists, for example verapamil, are found useful in combination withantineoplastic agents to establish chemosensitivity in tumor cellsresistant to accepted chemotherapeutic agents and to potentiate theefficacy of such compounds in drug-sensitive malignancies.

In view of their useful pharmacological properties, the components ofthe combinations according to the invention, i.e. the one or more othermedicinal agent and the compound according to the present invention maybe formulated into various pharmaceutical forms for administrationpurposes. The components may be formulated separately in individualpharmaceutical compositions or in a unitary pharmaceutical compositioncontaining all components.

The present invention therefore also relates to a pharmaceuticalcomposition comprising the one or more other medicinal agent and thecompound according to the present invention together with apharmaceutical carrier.

The present invention further relates to the use of a combinationaccording to the invention in the manufacture of a pharmaceuticalcomposition for inhibiting the growth of tumour cells.

The present invention further relates to a product containing as firstactive ingredient a compound according to the invention and as furtheractive ingredient one or more anticancer agent, as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of patients suffering from cancer.

The one or more other medicinal agents and the compound according to thepresent invention may be administered simultaneously (e.g. in separateor unitary compositions) or sequentially in either order. In the lattercase, the two or more compounds will be administered within a period andin an amount and manner that is sufficient to ensure that anadvantageous or synergistic effect is achieved. It will be appreciatedthat the preferred method and order of administration and the respectivedosage amounts and regimes for each component of the combination willdepend on the particular other medicinal agent and compound of thepresent invention being administered, their route of administration, theparticular tumour being treated and the particular host being treated.The optimum method and order of administration and the dosage amountsand regime can be readily determined by those skilled in the art usingconventional methods and in view of the information set out herein.

The weight ratio of the compound according to the present invention andthe one or more other anticancer agent(s) when given as a combinationmay be determined by the person skilled in the art. Said ratio and theexact dosage and frequency of administration depends on the particularcompound according to the invention and the other anticancer agent(s)used, the particular condition being treated, the severity of thecondition being treated, the age, weight, gender, diet, time ofadministration and general physical condition of the particular patient,the mode of administration as well as other medication the individualmay be taking, as is well known to those skilled in the art.

Furthermore, it is evident that the effective daily amount may belowered or increased depending on the response of the treated subjectand/or depending on the evaluation of the physician prescribing thecompounds of the instant invention. A particular weight ratio for thepresent compound of formula (I) and another anticancer agent may rangefrom 1/10 to 10/1, more in particular from 1/5 to 5/1, even more inparticular from 1/3 to 3/1.

The platinum coordination compound is advantageously administered in adosage of 1 to 500 mg per square meter (mg/m²) of body surface area, forexample 50 to 400 mg/m², particularly for cisplatin in a dosage of about75 mg/m² and for carboplatin in about 300 mg/m² per course of treatment.

The taxane compound is advantageously administered in a dosage of 50 to400 mg per square meter (mg/m²) of body surface area, for example 75 to250 mg/m², particularly for paclitaxel in a dosage of about 175 to 250mg/m² and for docetaxel in about 75 to 150 mg/m² per course oftreatment.

The camptothecin compound is advantageously administered in a dosage of0.1 to 400 mg per square meter (mg/m²) of body surface area, for example1 to 300 mg/m², particularly for irinotecan in a dosage of about 100 to350 mg/m² and for topotecan in about 1 to 2 mg/m² per course oftreatment.

The anti-tumour podophyllotoxin derivative is advantageouslyadministered in a dosage of 30 to 300 mg per square meter (mg/m²) ofbody surface area, for example 50 to 250 mg/m², particularly foretoposide in a dosage of about 35 to 100 mg/m² and for teniposide inabout 50 to 250 mg/m² per course of treatment.

The anti-tumour vinca alkaloid is advantageously administered in adosage of 2 to 30 mg per square meter (mg/m²) of body surface area,particularly for vinblastine in a dosage of about 3 to 12 mg/m², forvincristine in a dosage of about 1 to 2 mg/m², and for vinorelbine indosage of about 10 to 30 mg/m² per course of treatment.

The anti-tumour nucleoside derivative is advantageously administered ina dosage of 200 to 2500 mg per square meter (mg/m²) of body surfacearea, for example 700 to 1500 mg/m², particularly for 5-FU in a dosageof 200 to 500 mg/m², for gemcitabine in a dosage of about 800 to 1200mg/m² and for capecitabine in about 1000 to 2500 mg/m² per course oftreatment.

The alkylating agents such as nitrogen mustard or nitrosourea isadvantageously administered in a dosage of 100 to 500 mg per squaremeter (mg/m²) of body surface area, for example 120 to 200 mg/m²,particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m²,for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg, for carmustinein a dosage of about 150 to 200 mg/m², and for lomustine in a dosage ofabout 100 to 150 mg/m² per course of treatment.

The anti-tumour anthracycline derivative is advantageously administeredin a dosage of 10 to 75 mg per square meter (mg/m²) of body surfacearea, for example 15 to 60 mg/m², particularly for doxorubicin in adosage of about 40 to 75 mg/m², for daunorubicin in a dosage of about 25to 45 mg/m², and for idarubicin in a dosage of about 10 to 15 mg/m² percourse of treatment.

The antiestrogen agent is advantageously administered in a dosage ofabout 1 to 100 mg daily depending on the particular agent and thecondition being treated. Tamoxifen is advantageously administered orallyin a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day,continuing the therapy for sufficient time to achieve and maintain atherapeutic effect. Toremifene is advantageously administered orally ina dosage of about 60 mg once a day, continuing the therapy forsufficient time to achieve and maintain a therapeutic effect.Anastrozole is advantageously administered orally in a dosage of about 1mg once a day. Droloxifene is advantageously administered orally in adosage of about 20-100 mg once a day. Raloxifene is advantageouslyadministered orally in a dosage of about 60 mg once a day. Exemestane isadvantageously administered orally in a dosage of about 25 mg once aday.

Antibodies are advantageously administered in a dosage of about 1 to 5mg per square meter (mg/m²) of body surface area, or as known in theart, if different. Trastuzumab is advantageously administered in adosage of 1 to 5 mg per square meter (mg/m²) of body surface area,particularly 2 to 4 mg/m² per course of treatment.

These dosages may be administered for example once, twice or more percourse of treatment, which may be repeated for example every 7, 14, 21or 28 days.

The compounds of formula (I), the pharmaceutically acceptable additionsalts, in particular pharmaceutically acceptable acid addition salts,and stereoisomeric forms thereof can have valuable diagnostic propertiesin that they can be used for detecting or identifying the formation of acomplex between a labelled compound and other molecules, peptides,proteins, enzymes or receptors.

The detecting or identifying methods can use compounds that are labelledwith labelling agents such as radioisotopes, enzymes, fluorescentsubstances, luminous substances, etc. Examples of the radioisotopesinclude ¹²⁵I, ¹³¹I, ³H and ¹⁴C. Enzymes are usually made detectable byconjugation of an appropriate substrate which, in turn catalyses adetectable reaction. Examples thereof include, for example,beta-galactosidase, beta-glucosidase, alkaline phosphatase, peroxidaseand malate dehydrogenase, preferably horseradish peroxidase. Theluminous substances include, for example, luminol, luminol derivatives,luciferin, aequorin and luciferase.

Biological samples can be defined as body tissue or body fluids.Examples of body fluids are cerebrospinal fluid, blood, plasma, serum,urine, sputum, saliva and the like.

General Synthetic Routes

The following examples illustrate the present invention but are examplesonly and are not intended to limit the scope of the claims in any way.

EXPERIMENTAL PART

Hereinafter, the term ‘CH₃CN’ means acetonitrile, ‘DCM’ meansdichloromethane, ‘TBAF’ means tetrabutylammonium fluoride, ‘K₂CO₃’ meanspotassium carbonate, ‘MgSO₄’ means magnesium sulphate, ‘MeOH’ meansmethanol, ‘EtOH’ means ethanol, ‘EtOAc’ means ethyl acetate, ‘Et₃N’means triethylamine, ‘HOBt’ means 1-hydroxy-1H-benzotriazole, ‘DPPP’means 1,3-propanediylbis[diphenylphosphine, ‘DIPE’ means diisopropylether, ‘THF’ means tetrahydrofuran, ‘NH₄Cl’ means ammonium chloride,‘Pd(PPh₃)₄’ means tetrakis(triphenylphosphine)palladium, ‘DIPEA’ meansN-ethyl-N-(1-methylethyl)-2-propylamine, ‘DMF’ meansN,N-dimethylformamide, ‘NaH’ means sodium hydride, ‘Pd₂(dba)₃’ meanstris(dibenzylideneacetone) dipalladium (0), ‘HOAc’ means acetic acid,‘PPh₃’ means triphenylphosphine, ‘NH₄OH’ means ammonium hydroxide,‘TBDMSCI’ means tert-butyldimethylsilyl chloride, ‘S-Phos’ meansdicyclohexyl(2′,6′-dimethoxy[1,1′-biphenyl]-2-yl)-phosphine, ‘X-Phos’meansdicyclohexyl[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]-phosphine,‘Na₂SO₄′ means sodium sulfate, ‘i-PrOH’ means 2-propanol, ‘t-BuOH’ means2-methyl-2-propanol, ‘K₃PO₄’ means potassium phosphate, MP means meltingpoint.

A. Preparation of the Intermediates Example A1 a-1) Preparation ofIntermediate 1

7-bromo-2(1H)-quinoxalinone (47.2 g; 210 mmol) was added to phosphorusoxychloride (470 mL). The reaction mixture was stirred at 100° C. for 2hours, cooled down to room temperature and evaporated to dryness. Thecrude product was taken up into DCM and poured onto ice, water and K₂CO₃powder. The mixture was filtered over celite. The celite was washedtwice with DCM. The organic layer was decanted, dried over MgSO₄,filtered and evaporated to dryness to give 49 g (96%) of intermediate 1(grey solid). MP=146° C.

Intermediate 1 was alternatively also prepared using the followingprocedure:

Thionyl chloride (407.5 mL; 5.59 mol), then N,N-dimethylformamide (34.6mL; 0.45 mol) were added dropwise to a mixture of7-bromo-2(1H)-quinoxalinone (500 g; 2.24 mol) in toluene (7.61 L). Thereaction mixture was stirred at 80° C. for 17 hours then cooled to 35°C. and poured cautiously onto water. The bi-phasic mixture was stirredfor 30 minutes and then decanted. The organic layer was evaporated todryness and the residue crystallized in methyl-tert-butyl ether,filtered and the precipitate washed with methyl-tert-butyl ether anddried to give 407 g (74.7%) of intermediate 1. Filtrate was evaporatedand re-crystallized in methyl-tert-butyl ether to provide a secondfraction of 72 g (13.2%) of intermediate 1.

b-1) Preparation of Intermediate 2

Under N₂, intermediate 1 (20 g; 82.1 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(17.1 g; 82.1 mmol), 2M sodium carbonate aqueous solution (410.1 mL;82.1 mmol) in ethylene glycol dimethyl ether (200 mL) were degassed bybubbling nitrogen through for 15 minutes.Tetrakis(triphenylphosphine)palladium (0) (0.95 g; 0.82 mmol) was addedand heated at reflux for 15 hours. The reaction mixture was poured intowater and extracted with EtOAc. The organic layer was dried over MgSO₄,filtered and evaporated to dryness to give 29.9 g. The crude compoundwas purified by chromatography over silica gel (Irregular SiOH, 20-45μm, 1000 g MATREX; mobile phase 0.1% NH₄OH, 98% DCM, 2% CH₃OH). The purefractions were collected and concentrated till dryness to give 19.5 g(82%) of intermediate 2. MP=172° C.

Intermediate 2 was alternatively also prepared using the followingprocedure:

Intermediate 1 (502 g; 2.06 mol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(450.42 g; 2.16 mol), triphenylphosphine (10.82 g; 0.041 mol) andpalladium(II)acetate were added to a mixture of sodium carbonate (240.37g; 2.267 mol), 1,2-dimethoxyethane (5.48 L) and water (1.13 L). Thereaction mixture was stirred at reflux for 20 hours, then1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(42.9 g; 0.206 mol) was added and the reaction mixture refluxed untilcomplete conversion (4 hours). The reaction mixture was poured out inwater, stirred for 2 hours at room temperature, filtered and theprecipitate was washed with water. The precipitate was then trituratedin methanol and filtered. The precipitate was washed with methanol anddried to give 532.2 g (89%) of intermediate 2 (off-white powder).

Intermediate prepared according to the above protocol starting from

c-1) Preparation of Intermediate 3

A mixture of intermediate 2 (20 g; 69.2 mmol), 3,5-dimethoxyaniline(10.6 g; 69.2 mmol), sodium tert-butoxide (20 g; 0.21 mol) and1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine (2.2 g; 3.5mmol) in dioxane (500 mL) was degassed at room temperature under N₂flow. After 10 minutes, palladium(II) acetate (0.78 g; 3.5 mmol) wasadded portionwise at room temperature under N₂ flow. The reactionmixture was heated at 90° C. overnight. The reaction mixture was cooledto room temperature and partitioned between water and EtOAc. The organiclayers were combined, dried over MgSO₄, filtered and concentrated togive 40 g of crude compound. This residue was taken up into DCM/Et₂O(3/7) and the mixture was stirred for 30 minutes. The precipitate wasfiltered off and dried to give 20 g of intermediate 3 (brown solid). Thefiltrate was evaporated to dryness to give 40 g of a crude compoundwhich was purified by chromatography over silica gel (Irregular SiOH,20-45 μm, 450 g MATREX; Mobile phase 0.1% NH₄OH, 98% DCM, 2% CH₃OH). Thepure fractions were concentrated to give 4.2 g of intermediate 3 (brownsolid). MP=199° C. (DSC).

Overall yield=96.8%.

Intermediate prepared according to the above protocol starting from

Intermediate 3 was alternatively also prepared using the followingprocedure.

A mixture of intermediate 2 (80 g; 277 mmol), 3,5-dimethoxyaniline (47.6g; 304 mmol) and cesium carbonate (108.2 g; 332 mmol) in1,2-dimethoxyethane (1.1 L) was stirred at 80° C. under N₂ flow and thencooled to room temperature (solution A). In another flask under N₂, amixture of palladium(II)acetate (0.62 g; 2.8 mmol) andracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (1.76 g; 2.8 mmol)was stirred at 40° C. for 15 minutes and then added to solution A at 35°C. The new reaction mixture was stirred at 80° C. for 20 hours, cooledto 50° C. and water was added (1.11 L). The reaction mixture was seededwith crystals of intermediate 3 and extra water (0.55 L) was addedbefore cooling to room temperature. The precipitate was filtered off andwashed with water, then recrystallized in isopropylalcohol (withseeding). The prepcipitate was filtered off, washed withdiisopropylether and dried to provide 79.2 g (79.2%) of intermediate 3.

Intermediate 3 was alternatively also prepared usinq the followinqprocedure.

a-2) Preparation of Intermediate 4

2-Chloro-7-nitroquinoxaline (27.8 g, 133 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(30.4 g, 146 mmol), 2M Na₂CO₃ aqueous solution (66.3 mL, 133 mmol) inethylene glycol dimethyl ether (330 mL) were degassed with N₂ for 15minutes. Tetrakis(triphenylphosphine)palladium (0) (1.5 g, 1.33 mmol)was added and the reaction mixture was heated at 100° C. for 7 hours.The reaction was poured into water. The precipitate was filtered off,taken-up with EtOAc, then filtered and dried under vacuum to give 31.4 g(93%) of intermediate 4 (yellow solid). MP=231° C. (DSC).

Intermediate prepared according to the above protocol starting from

b-2) Preparation of Intermediate 5

A mixture of intermediate 4 (15.7 g, 61.5 mmol) and Raney nickel (16 g)in CH₃OH (380 mL) and THF (60 mL) was hydrogenated under a 3 barspressure overnight. The reaction mixture was filtered on a celite padwhich was washed 3 times with CH₃OH/DCM (50/50), then several times witha mixture of MeOH/acetone. The combined filtrates were evaporated tilldryness to give 13.1 g (95%) of intermediate 5 (brown solid). MP=240° C.(DSC).

Intermediate prepared according to the above protocol starting from

Intermediate 5 was alternatively also prepared using the followingprocedure.

A 200 mL stainless steel autoclave was charged under N₂ atmosphere withintermediate 2 (5 g, 17.3 mmol), NH₄OH (100 mL) and Cu₂O (0.1 g) Theautoclave was closed and the reaction was carried out for 16 hours at atemperature of 150° C. The reaction mixture was extracted with DCM, theorganic layer was washed with water, dried (MgSO₄) and filtered. Thefiltrate was evaporated till dryness and the residue was purified bychromatography over silica gel (kromasil C18 100A 5 μm, Eka nobel;mobile phase, from 90% of a 0.25% solution of ammonium bicarbonate inwater, 10% MeOH to 100% MeOH). The pure fractions were collected to give2.4 g (61.6%) of intermediate 5.

c-2) Preparation of Intermediate 3

The experiment has been performed 3 times on the following amount.

A mixture of intermediate 5 (2.12 g, 9.4 mmol),1-bromo-3,5-dimethoxybenzene (2.25 g, 10.4 mmol), sodium tert-butoxide(2.71 g, 28.3 mmol) and1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine](0.29 g,0.47 mmol) in ethylene glycol dimethyl ether (40 mL) was degassed withN₂ for 10 minutes. Palladium(II) acetate (0.21 g, 0.94 mmol) was addedand the mixture was heated at 135° C. for 60 minutes under microwaveirradiation The mixture was cooled to room temperature, poured into H₂Oand EtOAc. The 3 experiments were combined for the work up. The mixturewas filtered over celite. The filtrate was extracted with EtOAc. Thecombined organic layers were dried over MgSO₄, filtered and evaporatedto dryness to give 11.3 g of crude compound. The residue was purified bychromatography over silica gel (Irregular SiOH, 20-45 μm, (450 g)MATREX; mobile phase 0.1% NH₄OH, 95% DCM, 5% iPrOH). The pure fractionswere collected and the solvent was evaporated, yielding 7.6 g (74%) ofintermediate 3 (brown solid).

Intermediate prepared according to the above protocol starting from

a-4) Preparation of Intermediate 6

Tert-butyldimethylsilyl chloride (2.096 g, 13.9 mmol) was added to3-chloro-5-methoxybenzenemethanol (2 g, 11.6 mmol) in DCM (40 mL) at 0°C., followed by imidazole (2.5 g, 36.85 mmol). The reaction mixture wasslowly allowed to warm to room temperature and stirred overnight. Thereaction mixture was partitioned between EtOAc and water. The 2 phaseswere separated, the organic phase was dried (MgSO₄), filtered andconcentrated to give an oil which solidified on standing. The residuewas purified by chromatography over silica gel (Irregular SiOH, 15-40μm, 90 g; mobile phase 30% EtOAc, 70% pentane). The fractions werecollected and the solvent was evaporated, yielding 2.56 g (77%) ofintermediate 6.

b-4) Preparation of Intermediate 7

Intermediate 6 (1.39 g, 3.9 mmol), intermediate 5 (0.7 g, 3.1 mmol),Cs₂CO₃ (3 g, 0.3 mmol), tris(dibenzilideneacetone)dipalladium (0.28 g,0.3 mmol) and X-Phos (0.33 g, 0.68 mmol) in t-BuOH (20 mL) were stirredat 100° C. under microwave irradiation for 3 hours. The reaction mixturewas filtered through celite and the filtrate was concentrated to −1/3 ofthe initial volume. H₂O and EtOAc were added and the organic phase wasseparated, dried (MgSO₄), filtered and concentrated. The residue waspurified by chromatography over silica gel (Hyperprep C18 HS BDS100A 8mu (Shandon); mobile phase gradient from 70% of a 0.25% solution ofammonium bicarbonate in water/30% CH₃CN to 10% of a 0.25% solution ofammoniumbicarbonate in water/90% CH₃CN). The pure fractions werecollected and the solvent was evaporated, yielding 418 mg ofintermediate 7.

a-5) Preparation of Intermediate 8

A mixture of intermediate 13 (see hereinafter) (9.45 g, 29.9 mmol),1-(1-methylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(8.48 g, 35.9 mmol), potassium phosphate (15.88 g, 74.8 mmol) anddicyclohexyl(2′,6′-dimethoxy[1,1′-biphenyl]-2-yl)phosphine (1.23 g, 3.0mmol) in dioxane (125 mL) and H₂O (25 mL) was degassed at roomtemperature under N₂ flow. After 10 minutes, Pd(PPh₃)₄ (1.73 g, 1.5mmol) was added portionwise. The reaction mixture was then heated at 80°C. overnight, then cooled to room temperature and poured out into icewater. EtOAc was added and the organic layer was washed with water, thenwith brine, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (20.2 g) was purified by chromatography over silica gel(Irregular SiOH, 20-45 μm, 1000 g MATREX; mobile phase 95% DCM, 5% MeOH,0.1% NH₄OH). The product fractions were collected and the solvent wasevaporated, yielding 10 g (85%). of intermediate 8.

Example A2 Preparation of Intermediate 9

NaH (1.77 g; 44.27 mmol) was added portionwise to a solution ofintermediate 3 (8 g; 22.13 mmol) in N,N-dimethylformamide (160 mL) at 5°C. under N₂ flow. The reaction mixture was stirred at 5° C. for 1 hour.Then, (2-bromoethoxy)-tert-butyldimethylsilane (9.5 mL; 44.27 mmol) wasadded dropwise at 5° C. under N₂ flow. The reaction mixture was stirredfor 1 hour at 5° C. then, allowed to warm to room temperature andstirred overnight. The reaction was poured out into ice water and EtOAcwas added. The organic layer was separated, washed with brine, dried(MgSO₄), filtered and the solvent was evaporated to dryness to give 17 gof a residue which was purified by chromatography over silica gel(Irregular SiOH, 15-40 μm, 200 g; mobile phase gradient from 100% DCM to96% DCM, 4% MeOH).

The pure fractions were collected and concentrated yielding 11 g (95%)of intermediate 9.

Intermediate 9 was alternatively also prepared using the followingprocedure.

a) Preparation of Intermediate 40

A mixture of 3,5-dimethoxyphenylamine (250 g; 1.63 mol), cesiumcarbonate (319 g; 0.98 mol) and water (0.33 L) in 1,2-dimethoxyethane (2L) was heated to 60° C. Then carbonochloridic acid, 2-chloroethyl ester(250 g; 1.75 mol) was added dropwise at this temperature over 1 hour. Asolution of potassium hydroxide (458 g; 8.2 mol) in water (1.3 L) wasadded in one portion. The reaction mixture was stirred at 60° C. for 30minutes, then heated at 100° C. to distill off 1,2-dimethoxyethane usinga Dean-Starck trap. The residue was cooled to 50° C. and extracted withmethyl-tert-butyl ether (1.14 L). The organic layer was washed withwater, dried (MgSO₄), filtered and the filtrate was evaporated tilldryness. The residue was crystallized in a mixture of methyl-tert-butylether and heptane. The precipitate was filtered off and dried to provide241.8 g (75%) of intermediate 40.

b) Preparation of Intermediate 41

TBDMSCI (262.7 g; 1.74 mol) was added portionwise over 10 minutes, undera N₂ atmosphere, to a solution of intermediate 40 (327.4 g; 1.66 mol)and 1H-imidazole (124.3 g; 1.825 mol) in DCM (3.3 L) at roomtemperature. Upon completion of the reaction, water (3.3 L) was addedand the organic layer was decanted, washed with water (3.3 L), dried(MgSO₄), filtered and the filtrate was filtered on silica gel andconcentrated to give 496 g (95.9%) of intermediate 41, used crude forthe next step.

c) Preparation of Intermediate 9

Under an inert atmosphere, a solution of palladium(II) acetate (1.16 g;5.2 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (4.4 g;6.9 mmol) in 1,2-dimethoxyethane (52 mL) was added at room temperatureto a solution of intermediate 2 (100 g; 346 mmol), intermediate 41(118.5 g; 380.5 mmol) and cesium carbonate (135 g; 415 mmol) in1,2-dimethoxyethane (1.4 L). The reaction mixture was heated at 80° C.over 1 hour, stirred at this temperature for 2 hours and refluxedovernight. Water (0.5 L) and DCM (1.5 L) were then added at roomtemperature and the organic layer was separated, washed with water andevaporated till dryness to provide crude intermediate 9 (21 g) which candirectly be used into the next step.

Example A3 Preparation of Intermediate 10

Methanesulfonyl chloride (3.8 mL; 49.33 mmol) was added dropwise to asolution of compound 1 (10 g; 24.66 mmol) and Et₃N (8.58 mL; 61.67 mmol)in DCM (250 mL) at 5° C. under N₂ flow. The reaction mixture was stirredat 5° C. for 1 hour, then 1 hour at room temperature. The reactionmixture was poured out into ice water and DCM was added. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated to dryness (30° C.). The residue was precipitated by additionof DIPE. The solid was filtered yielding, after drying, 10.09 g (94%) ofintermediate 10 (red solid). MP=161° C. (kofler).

Intermediate prepared according to the starting above protocol from

com- pound 3

Example A4 a-1) Preparation of Intermediate 11

NaH (1.1 g; 27.67 mmol) was added portionwise to a solution ofintermediate 3 (5 g; 13.83 mmol) in N,N-dimethylformamide (80 mL) at 5°C. under N₂ flow. The reaction mixture was stirred at 5° C. for 1 hourthen (3-bromopropoxy) (1,1-dimethylethyl)dimethylsilane (6.41 mL, 27.67mmol) was added dropwise at 5° C. under N₂ flow. The reaction mixturewas stirred 1 hour at 5° C. then warmed to room temperature and stirredovernight. The reaction was poured out into ice water and EtOAc wasadded. The organic layer was separated, dried (MgSO₄), filtered and thesolvent was evaporated to dryness to give a crude residue (9.1 g).Purification by chromatography over silica gel (Irregular SiOH, 15-40μm; mobile phase gradient from 100% DCM to 98% DCM, 2% MeOH) affordedafter concentration of the pure fractions 7 g (94%) of intermediate 11.

Intermediate 11 was alternatively also prepared using the followingprocedure. NaH (31.65 g, 60% w/w in oil; 0.79 mol) was added portionwiseover 15 minutes to a cooled (−2° C.) solution of intermediate 3 (130 g;0.36 mol) in N,N-dimethylacetamide. The reaction mixture was stirred at−2° C. for 30 minutes before addition of (3-bromopropoxy)(1,1-dimethylethyl)dimethylsilane (100.2 g; 0.4 mol). The reactionmixture was further stirred at −2° C. for 1.5 hours and overnight atroom temperature after removal of the cooling system. The reactionmixture was then poured out in water (2.5 L), DCM (1 L) was added andthe pH was adjusted to 6 with acetic acid. The layers were separated,the organic layer was washed with water, dried (MgSO₄), filtered andconcentrated till dryness to provide 167.2 g (87%) of intermediate 11.

Intermediate prepared according to the above protocol starting from

a-2) Preparation of Intermediate 12

7-Bromo-2(1H)-quinoxalinone (25 g; 0.11 mol), 3,5-dimethoxyaniline(20.42 g; 0.133 mol), sodium tert-butoxide (32 g; 0.333 mol),1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine](6.9 g;0.011 mol) in ethylene glycol dimethyl ether (400 mL) were degassed withN₂ for 10 minutes. Palladium(II) acetate (2.5 g; 0.01 μmol) was addedand the mixture refluxed for 5 hours. The reaction mixture was cooled toroom temperature and the solvent was concentrated under vacuum to 150mL. The residue was poured onto ice water (1.5 L) under stirring andEtOAc was added (100 mL). The suspension was stirred at room temperatureovernight and the precipitate was filtered off, washed with water, thenCH₃CN and dried yielding 33 g of intermediate 12.

b-2-a) Preparation of Intermediate 13

Intermediate 12 (30 g; 0.1 mol) was added portionwise at roomtemperature to phosphorus oxychloride (415 mL). Then the reactionmixture was heated at 80° C. and stirred at this temperature for 40minutes. The mixture was cooled to room temperature and phosphorousoxychloride was removed under vacuum. The residue was carefully pouredonto an aqueous solution of K₂CO₃. The aqueous layer was extracted withDCM. The organic layer was dried (MgSO₄), filtered and evaporated todryness. The residue was purified by chromatography over silica gel(Irregular SiOH, 15-40 μm, 450 g; mobile phase, gradient from 100% DCMto 98% DCM, 2% MeOH). The product fractions were collected and thesolvent was evaporated, to give 22.6 g (70%) of intermediate 13. MP=137°C. (Kofler).

Intermediate 13 was Alternatively Also Prepared Usinq the FollowinqProcedure.

b-2-b) N-Chlorosuccinimide (11.23 g; 84.08 mmol) was added portionwiseat room temperature to a suspension of PPh₃ (22.05 g, 84.08 mmol) indioxane (500 mL). The reaction mixture was stirred for 30 minutes.Intermediate 12 (5 g; 16.8 mmol) was added and the reaction mixture wasrefluxed for 5 hours, then cooled to room temperature and basified withEt₃N (10 mL) under stirring. The suspension was stirred overnight andthe insoluble material was removed by filtration. The filtrate wasconcentrated and the residue (35 g) was purified by chromatography oversilica gel (Irregular SiOH, 15-40 μm, 400 g; mobile phase 100% DCM). Thepure fractions were collected and evaporated to dryness, yielding 2 g(37%) of intermediate 13.

c-2) Preparation of Intermediate 14

NaH (1.48 g; 37.1 mmol) was added portionwise to a solution ofintermediate 13 (9 g; 28.50 mmol) in DMF (100 mL) at 5° C. under N₂flow. The reaction mixture was stirred at 5° C. for 1 hour, then,(3-bromopropoxy)(1,1-dimethylethyl)dimethylsilane (8.58 mL; 37.1 mmol)was added dropwise at 5° C. under N₂ flow. The reaction mixture wasstirred for 1 hour at 5° C. then allowed to warm to room temperature andstirred for 4 hours. The reaction was poured out into ice water andEtOAc was added. The organic layer was separated, washed with brine,dried (MgSO₄), filtered and the solvent was evaporated. The residue(17.5 g) was purified by chromatography over silica gel (Irregular SiOH,20-45 μm, 1000 g, MATREX; mobile phase 98% DCM, 2% Cyclohexane). Thepure fractions were collected and the solvent was evaporated, yielding13.3 g (95%) of intermediate 14.

Intermediate prepared according to the above protocol starting from

d-2) Preparation of Intermediate 11

A mixture of intermediate 14 (15.5 g; 31.8 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(9.9 g; 47.6 mmol), potassium phosphate (13.5 g; 63.5 mmol) anddicyclohexyl(2′,6′-dimethoxy[1,1′-biphenyl]-2-yl)phosphine (1.3 g; 3.2mmol) in dioxane (380 mL) and H₂O (150 mL) was stirred at roomtemperature under N₂ flow. After 10 minutes, Pd₂(dba)₃ (1.45 g; 1.6mmol) was added portionwise at room temperature under N₂ flow. Thereaction mixture was heated at 80° C. overnight. The reaction mixturewas cooled to room temperature and poured out into ice water. Themixture was filtered over celite. Celite was washed with DCM. Theorganic layer was washed with brine, dried (MgSO₄), filtered and thesolvent was evaporated, yielding 21 g (99%) of intermediate 11.

Intermediate prepared according to the above protocol starting from

Example A5 a) Preparation of Intermediate 15

Methanesulfonyl chloride (3.53 mL, 45.77 mmol) was added dropwise to asolution of compound 3 (9.6 g, 22.88 mmol) and triethylamine (7.96 mL,57.21 mmol) in DCM (250 mL) at 5° C. under a N₂ flow. The reactionmixture was stirred for 1 hour allowing the temperature to rise to roomtemperature. The reaction mixture was poured out into ice water and DCMwas added. The organic layer was separated, dried (MgSO₄), filtered andthe solvent was evaporated to dryness. The crude residue was taken upinto DIPE. The precipitated was filtered yielding, after drying, 10.5 g(92%) of intermediate 15.

b) Preparation of Intermediate 16

Methanesulfonyl chloride (0.97 mL, 12.52 mmol) was added dropwise to asuspension of compound 2 (0.98 g, 2.50 mmol) and Et₃N (2.09 mL, 15.02mmol) in DCM (50 mL) at 5° C. under N₂. The mixture was stirred at roomtemperature for 3 hours. The solution was evaporated at room temperatureyielding 1.38 g of intermediate 16. The residue was used withoutpurification for the next step.

Intermediate prepared according to the above protocol starting from

c) Preparation of Intermediate 143

Methanesulfonyl chloride (519 μL, 6.7 mmol) was added dropwise to asolution of compound 389 (1.5 g, 3.35 mmol), triethylamine (1.2 mL, 8.4mmol), 4-dimethylaminopyridine (40.95 mg, 0.335 mmol) in DCM (50 mL) at5° C. under N₂ flow. The reaction mixture was stirred at 5° C. for 1hour, then at room temperature for 36 hours. Water and DCM were addedand the organic layer was washed with water, dried (MgSO₄), filtered andthe solvent was evaporated. The residue was crystallised fromacetonitrile and Et₂O. The resulting solid was filtered and dried togive 622 mg (35%) of a yellow solid intermediate 143.

Example A6 a-1) Preparation of Intermediate 17

NaH (16.88 g; 0.42 mol) in suspension in heptane was slowly added to asolution of intermediate 17a (100 g; 0.201 mol) and 1,1-dimethylethylester N-(2,2,2-trifluoroethyl)-carbamic acid (48.03 g; 0.241 mol) inN,N-dimethylacetamide (1 L) at 0° C. The reaction mixture was stirredfor 1 hour at 0° C., allowed to warm to room tempature in 1 hour andstirred at room temperature for 5 hours. The reaction mixture wascarefully quenched with water (1 L) and the solution was extracted twicewith DCM. The combined organic layers were washed with water, decantedand evaporated to dryness. The residue was dissolved in toluene, theorganic layer was washed with water and evaporated to dryness to provide147 g of intermediate 17 which was used without further purification inthe next step.

Intermediate 17 was Alternatively Also Prepared Using the FollowingProcedure

a-2) NaH (Ig; 24.94 mmol) was added portionwise to a solution ofintermediate 3 (4.5 g; 12.47 mmol) and intermediate 69 (5.02 g; 14.96mmol) in DMF (47 mL) at 5° C. The reaction mixture was heated at 60° C.for 1 hour, then cooled to room temperature, poured onto iced water andextracted with EtOAc. The organic layer was decanted, washed with waterthen brine, dried (MgSO₄), filtered and evaporated to dryness. Theresidue was combined with an analogously prepared product fraction(using 1.4 g of intermediate 3) and then purified by chromatography oversilica gel (Irregular SiOH, 15/40 μm) mobile phase gradient from 99%DCM/1% CH₃OH to 97% DCM/3% MeOH). The pure fractions were collected andevaporated to dryness yielding 5.8 g (77%) of intermediate 17. MP=113°C.

Intermediate prepared according to the above protocol starting from

Example A7 a) Preparation of Intermediate 18

NaH (830 mg; 20.75 mmol) was added portionwise to a solution ofintermediate 3 (5 g; 13.84 mmol) in N,N-dimethylformamide (150 mL) at 5°C. under N₂ flow. The reaction mixture was stirred at 5° C. for 1 hourthen a solution of 2-(3-bromopropoxy)tetrahydro-2H-pyran (3.5 mL; 20.75mmol) was added dropwise at 5° C. under N₂ flow. The reaction mixturewas stirred for 1 hour at 5° C., then allowed to warm to roomtemperature. The reaction was stirred at room temperature for 4 hours.The reaction was poured out into ice water and EtOAc was added. Theorganic layer was separated, washed with brine, dried (MgSO₄), filteredand the solvent was evaporated to give 8.46 g of intermediate 18.

Intermediate prepared according to the above protocol starting from

Example A8 a) Preparation of Intermediate 19

NaH (882 mg; 22.04 mmol) was added portionwise to a solution ofintermediate 13 (5.8 g; 18.4 mmol) in DMF (100 mL) under N₂ at 5° C. Thereaction mixture was stirred for 20 minutes and(bromomethyl)cyclopropane (2.2 mL; 22.04 mmol) was added dropwise. Themixture was stirred for another 20 minutes at 5° C., then at roomtemperature for 1.5 hour. The reaction mixture was poured into H₂O andextracted with EtOAc. The organic layer was dried (MgSO₄), filtered andevaporated to dryness, yielding 6.7 g (98%) of intermediate 19.

b) Preparation of Intermediate 20

A mixture of intermediate 19 (3 g; 8.1 mmol), 1-Boc-pyrazole-4-boronicacid pinacol ester (2.86 g; 9.7 mmol), potassium phosphate (3.44 g; 16.2mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.33 g; 0.811mmol) in dioxane (60 mL) and H₂O (6 mL) was stirred at room temperatureunder N₂ flow. After 10 minutes, tris(dibenzylideneacetone)dipalladium(0.3 g; 0.41 mmol) was added portionwise at room temperature and themixture was heated at 80° C. overnight. The reaction mixture was cooledto room temperature and poured out into ice water. EtOAc was added andthe mixture was filtered through a layer of celite. The celite waswashed with EtOAc, then the filtrate was extracted with EtOAc, washedwith brine, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue was purified by chromatography over silica gel (Irregular SiOH,15-40 μm, 300 g MERCK; mobile phase 0.05% NH₄OH, 99% DCM, 1% iPrOH). Thepure fractions were collected and evaporated to dryness, yielding 1.48 g(36%) of intermediate 20.

Intermediate prepared according to the above protocol starting from

Example A9 a-1) Preparation of Intermediate 21

7-Bromo-2-chloroquinoxaline (10 g, 41.1 mmol),1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(11.42 g, 41.1 mmol), sodium carbonate 2M (20.5 mL, 41.1 mmol) inethylene glycol dimethyl ether (100 mL) were degassed with N₂ for 15minutes, Pd(PPh₃)₄ (1.4 g, 1.2 mmol) was added and heated at reflux for20 hours. The reaction mixture was cooled to room temperature, pouredinto H₂O and EtOAc. The precipitate was filtered and dried under vacuumto give 12 g (84%) of intermediate 21.

Intermediate 21 was alternatively also prepared using the followingprocedure. a-2) Trifluoroacetic acid (5.55 μl; 0.075 mmol) was addeddropwise to a solution of 7-bromo-2-(1H-pyrazol-4-yl)quinoxaline (410mg; 1.5 mmol) and 3,4-dihydro-2H-pyran (0.16 mL; 1.8 mmol) in toluene (4mL) and the reaction mixture was heated to 60° C. for 2 days, thencooled to room temperature and evaporated till dryness, yielding 550 mgof intermediate 21.

b) Preparation of Intermediate 22

A mixture of intermediate 21 (1.5 g; 4.2 mmol), aniline (0.58 mL; 6.23mmol), sodium tert-butoxide (1.2 g; 12.5 mmol) and1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine](260 mg;0.42 mmol) in ethylene glycol dimethyl ether (45 mL) was degassed withN₂ for 30 minutes, then palladium(II) acetate (93.7 mg; 0.42 mmol) wasadded. The reaction mixture was refluxed for 4 hours. H₂O/ice was addedand the product was extracted with EtOAc. The organic layer was washedwith H₂O, a saturated aqueous solution of NaCl, dried (MgSO₄), filteredand the solvent was evaporated till dryness. The crude product waspurified by chromatography over silica gel (Irregular SiOH 15-40 μm, 90g; mobile phase gradient from 99% DCM/1% MeOH to 97% DCM/3% MeOH/0.1%NH₄OH). The pure fractions were collected and the solvent was evaporatedtill dryness yielding 1.1 g (70%) of intermediate 22 A fraction (0.7 g)was re-purified by chromatography over silica gel (Sunfire Silica 5 μm150×30.0 mm; mobile phase Gradient from 100% DCM to 0.4% NH₄OH, 96% DCM,4% CH₃OH). The pure fractions were collected and the solvent wasevaporated till dryness, yielding 0.071 g (4.5%) of intermediate 22.

c) Preparation of Compound 123

NaH (116.3 mg; 2.9 mmol) was added portionwise to a solution ofintermediate 22 (0.9 g; 2.4 mmol) in DMF (14 mL) at 5° C. The reactionmixture was stirred for 30 minutes. (Bromomethyl)cyclopropane (0.28 mL;2.9 mmol) was added dropwise and the reaction mixture was stirred for 1hour at 5° C., then at room temperature overnight. The reaction mixturewas poured into H₂O and extracted twice with EtOAc. The organic layerwas washed with a saturated aqueous solution of NaCl, dried (MgSO₄),filtered and the solvent was evaporated till dryness. The crude productwas purified by chromatography over silica gel (Irregular SiOH, 30 g,15-40 μm; mobile phase 98% DCM/2% CH₃OH). The pure fractions werecollected and the solvent was evaporated till dryness to give 0.5 g(48%) of compound. A fraction (0.4 g) was re-purified by chromatographyover silica gel (Spherical SiOH, 10 μm, 60 g, PharmPrep MERCK; mobilephase 99% DCM, 1% MeOH). The pure fractions were collected and thesolvent was evaporated, yielding 85 mg (8%) of compound 123.

d) Preparation of Compound 54

At 5° C., HCl/i-PrOH (80 μl 5/6N, 0.4 mmol) was added to a solution ofcompound 123 (85 mg; 0.2 mmol) in CH₃OH (5 mL). The reaction mixture wasstirred at 5° C. for 4 hours. Diethyl ether (8 mL) was added and themixture was stirred for 30 minutes, then the precipitate was filteredand dried under vacuum, yielding 58 mg (71%) of compound 54 MP=138° C.(Kofler).

e) Preparation of Intermediate 23

The reaction was done under a nitrogen atmosphere. NaH (0.058 g; 1.46mmol) was added portionwise to a solution of compound 54 (0.25 g; 0.73mmol) in DMF (5 mL) at 5° C. The reaction mixture was stirred for 30minutes, then 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.23 mL; 1.46 mmol)was added dropwise and the reaction mixture was further stirredovernight at room temperature. The reaction mixture was poured into anaqueous solution of potassium carbonate and extracted with EtOAc. Theorganic layer was dried (MgSO₄), filtered and evaporated to dryness. Thecrude product was purified by chromatography over silica gel (IrregularSiOH, 15-40 μm 30 g; mobile phase 0.1% NH₄OH, 99% DCM, 1% CH₃OH). Thepure fractions were collected and the solvent was evaporated tilldryness, yielding 250 mg (72%) of intermediate 23.

Intermediate/compound prepared according to the above protocol startingfrom

7-bromo-2-(1H-pyrazol-4- yl)quinoxaline

Intermediate 691

used to prepare compound 691 according to B14A, was prepared in ananalogous way:

The experiment has been performed 4 times on the following amounts.

A mixture of compound 137 (HCl salt) (2 g; 4.6 mmol),2-bromoethoxy-t-butyl dimethylsilane (1.3 mL; 7.4 mmol) and K₂CO₃ (1.3g; 9.3 mmol) in CH₃CN (80 mL) was stirred at 80° C. for 24 hours. Thereaction was poured out into ice water and EtOAc was added. The organiclayers were combined, separated and washed with brine, dried (MgSO₄),filtered and the solvent was evaporated. The residue (12.3 g) waspurified by chromatography over silica gel (SiOH 15-40 μm, 450; mobilephase gradient from 0.5% NH₄OH, 97% DCM, 3% MeOH to 0.5% NH₄OH, 90% DCM,10% MeOH). The pure fractions were collected and concentrated to give 6g of intermediate 691

Example A10 Preparation of Intermediate 24

To a solution of intermediate 65 (1.1 g; 2.25 mmol) in THF (15 mL) andH₂O (15 mL) was added lithium hydroxide monohydrate (0.34 g; 4.5 mmol).The reaction mixture was stirred overnight at room temperature. THF wasevaporated and H₂O and HCl were added. The precipitate was filtered anddried, yielding 976 mg (94%) of intermediate 24.

Intermediate prepared according to the above protocol starting from

Example A11 Preparation of Intermediate 25

A solution of intermediate 2 (Ig; 0.35 mmol), cyclopropanemethylamine(0.51 g, 6.9 mmol)1,1′-[1,1′-Binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine](0.215 g,0.35 mmol) and sodium tert-butoxide (1.0 g, 10.4 mmol) inethyleneglycol-dimethylether (15 mL) was degassed with N₂ for 10minutes. Then palladium(II) acetate (47% Pd) (77.6 mg, 0.35 mmol) wasadded and the reaction was heated under microwave irradiation to 135° C.for 30 minutes. The reaction mixture was cooled to room temperature,then poured into an aqueous solution of K₂CO₃ and extracted with EtOAc.The organic layers were combined and dried (MgSO₄), filtered andevaporated to dryness. The residue was purified by chromatography oversilica gel (Irregular SiOH, 15-40 μm; mobile phase, gradient from 10%DCM to 95% DCM/5% MeOH/0.1% NH₄OH). The pure fractions were collectedand evaporated, yielding 710 mg (74%) of intermediate 25. MP=149° C.(kofler).

Example A12 a) Preparation of Intermediate 26

Methanesulfonyl chloride (61 μL, 0.78 mmol) was added dropwise to asolution of compound 24 (0.13 g, 0.26 mmol), Et₃N (0.18 mL, 1.3 mmol) inDCM (10 mL) at 5° C. under N₂. The solution was stirred for 1.5 hours at10° C. The solution was poured out into ice water, the organic layer wasextracted, dried (MgSO₄) and evaporated to dryness at room temperature,yielding 137 mg of intermediate 26.

b) Preparation of Intermediate 27

A solution of intermediate 26 (0.31 g; 0.0006 mol), phthalimide (0.17 g,0.0012 mol) and K₂CO₃ (0.21 g; 0.0015 mol) in 1-methyl-2-pyrrolidinone(10 mL) were heated at 150° C. for 15 hours. The mixture was cooled toroom temperature and evaporated to dryness. The residue was taken upwith DCM, then an aqueous K₂CO₃ solution (10%) were added. The organiclayer was separated, dried (MgSO₄), filtered and evaporated to dryness.The residue was purified by chromatography over silica gel (SphericalSiOH, 10 μm, 60 g PharmPrep MERCK; mobile phase 0.1% NH₄OH/99% DCM/1%MeOH). The product fractions were collected and the solvent wasevaporated, yielding 212 mg (63%) of intermediate 27.

Example A13 a) Preparation of Intermediate 28

Hydrazine monohydrate (2.57 mL, 0.083 mol) was added to a solution ofcompound 65 (3.71 g, 8.29 mmol) in EtOH (35 mL). The mixture was stirredovernight at reflux. Hydrazine monohydrate (2.57 mL, 0.083 mol) wasadded again and the mixture was refluxed for 15 hours. After coolingdown to room temperature, the precipitate was filtered off, washed withEtOH and dried to give 2.6 g (72%) of intermediate 28.

Example A14 a) Preparation of Intermediate 29

NaH (0.077 g; 2 mmol) was added portionwise to a solution of compound107(0.63 g; 1.2 mmol) in DMF (10 mL). The mixture was stirred at 10° C.for 60 minutes, then ethyl bromoacetate (0.16 mL, 1.45 mmol) was added.The resulting mixture was stirred at room temperature for 2 hours. Themixture was poured into water and the product was extracted with EtOAc.The organic layer was washed with water, brine, dried (MgSO₄), filteredand evaporated until dryness. The residue (Ig) was crystallized fromdiethyl ether. The precipitate was filtered and dried, yielding 0.55 g(75%) of intermediate 29.

Example A15 a) Preparation of Intermediate 30

To a mixture of intermediate 2 (700 mg; 2.4 mmol), intermediate 39 (781mg; 2.66 mmol), sodium tert-butoxide (698 mg; 7.3 mmol),1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine](151 mg;0.24 mmol) in dioxane (12 mL) was degassed at room temperature under N₂flow. After 10 minutes, palladium (II) acetate (109 mg; 0.48 mmol) wasadded at room temperature under N₂ flow. The reaction was performedunder microwave irradiation at 130° C. for 1 hour. The reaction mixturewas poured out onto ice water and filtered over celite. Celite waswashed with DCM. The organic layer was decanted, dried (MgSO₄), filteredand evaporated. The residue was purified by chromatography over silicagel (Irregular SiOH, 15-40 μm, 300 g MERCK; mobile phase 0.1% NH₄OH, 97%DCM, 3% iPrOH). The product fractions were collected and the solvent wasevaporated, yielding 320 mg (26%) of intermediate 30.

b) Preparation of Intermediate 31

Intermediate 30 (300 mg, 0.598 mmol) in HCl (3N) (10.96 mL, 33 mmol) andTHF (10 mL) was stirred at 65° C. for 2 hours, then for 6 hours at 70°C., and poured out onto ice. The solution was made basic with K₂CO₃powder and extracted with DCM. The organic layer was dried (MgSO₄),filtered and evaporated, yielding 270 mg (98%) of intermediate 31.

Example A16 a) Preparation of Intermediate 32

Acetic anhydride (3.24 mL) was added portionwise over ten minutes to astirred suspension of 3,5-dimethoxyaniline (5 g, 32.64 mmol) in toluene(25 mL). After stirring at room temperature for 17 hours, petroleumether was added and the precipitate collected by suction filtration anddried under vacuum. The crude product (6.1 g, 96%) was used in the nextstep without further purification.

b) Preparation of Intermediate 33

N-(3,5-dimethoxy-phenyl)-acetamide (intermediate 32) (15 g, 76.8 mmol)was dissolved in AcOH (50 mL). The solution was cooled to 0° C. and 32%aqueous hydrochloric acid solution (41 mL, 461 mmol) was added. Asolution of sodium chlorate (3.5 g, 33 mmol) in water (4 mL) was added.The mixture was stirred for 30 minutes at 0° C. The reaction mixture waspoured out onto ice and water and made basic with K₂CO₃ powder. Theprecipitate was filtered off and washed with water.

The residue was purified by chromatography over silica gel (IrregularSiOH, 15-40 μm, 300 g MERCK; mobile phase 80% DCM, 20% EtOAc) to give8.8 g (50%) of intermediate 33.

c) Preparation of Intermediate 34

Potassium hydroxide (10.7 g, 192 mmol) was added to a solution ofN-(2-Chloro-3,5-dimethoxy-phenyl)-acetamide (intermediate 33) (8.8 g,38.3 mmol) in EtOH (500 mL) and water (50 mL) and the reaction mixtureheated to reflux for 18 hours. Upon cooling, water was added (ca 30 mL)and the EtOH removed in vacuum. The residue was then partitioned betweenwater and diethyl ether. The organic layer was separated, dried (MgSO₄),filtered and concentrated to afford 7 g (97%) of intermediate 34 (whitesolid).

Example A17 Preparation of Intermediate 35

A mixture of 2,4-dimethoxy-6-nitrotoluene (2 g, 10.1 mmol) and nickel (2g) in MeOH (30 mL) was hydrogenated under a 3 bars pressure for 6 hours.The product was filtered over a celite pad which was washed 3 times witha solution of MeOH/DCM (50/50). The combined filtrates were evaporatedtill dryness to give 1.68 g (99%) of intermediate 35.

Example A18 a) Preparation of Intermediate 36

A mixture of 3-amino-5-methoxy-benzoic acid (300 mg, 1.8 mmol),1-hydroxybenzotriazole (292 mg, 2.1 mmol),N-Ethyl-N′-β-dimethylaminocarbodiimide hydrochloride (413 mg, 2.1 mmol),and ethyl amine (2.7 mL, 5.4 mmol, 2M in MeOH) in dimethylformamide (6mL) was stirred at room temperature overnight. The solvent wasevaporated under vacuum and the residue partitioned between DCM andwater. The organic layer was separated and the aqueous layer wasextracted with further DCM. The combined organic layers were dried(Na₂SO₄) and concentrated. The residue was purified by columnchromatography over silica gel eluting with 2% MeOH/DCM. The desiredproduct fractions were collected and the solvent was evaporated,yielding 150 mg (43%) of intermediate 36 (colourless oil).

b) Preparation of Intermediate 135

A mixture of 3-amino-5-fluorobenzoic acid (10 g; 64.5 mmol), methylaminein THF (96.7 mL; 193.4 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.8 g;77.4 mmol), 1-hydroxybenzotriazole (10.5 g; 77.4 mmol), inN,N-dimethylformamide (150 mL) was stirred at room temperature for 18hours. The reaction mixture was poured out into a solution of sodiumhydroxide 1 N and DCM was added. The organic layer was separated, washedwith water, dried (MgSO₄), filtered and the solvent was evaporated.

The aqueous layer was neutralized with concentrated HCl and extractedwith EtOAc. The organic layer was separated, dried (MgSO₄), filtered andevaporated till dryness to give 5 g of3-amino-5-methoxy-N-methyl-benzamide (intermediate 135).

Example A19 Preparation of Intermediate 37

A solution of deoxofluor in toluene (0.478 mmol; 0.176 mL) was addeddropwise to a solution of compound 124 (0.159 mmol; 90 mg) in DCM (8 mL)at 5° C. under N₂ flow. After 5 minutes, EtOH (a drop) was added. Themixture was stirred at 5° C. for 1 hour, then overnight at roomtemperature. The reaction mixture was poured out into ice water and DCMwas added. The mixture was basified with K₂CO₃ 10% and the organic layerwas separated, washed with brine, dried (MgSO₄), filtered and thesolvent was evaporated. The obtained residue (0.090 g) was purified bycolumn chromatography over silica gel (Irregular SiOH, 15/40 μm, 30 g;mobile phase gradient from 100% DCMto 97% DCM/3% MeOH). The productfractions were collected and the solvent was evaporated. The residue(0.070 g, 77%) was crystallized from diethyl ether/CH₃CN, filtered anddried under vacuum, yielding 0.055 g (60%) of intermediate 37.

Example A20 Preparation of Intermediate 38

In a round bottom flask, 3,5-dimethoxybenzenamine (500 mg, 3.26 mmol),3-oxetanone (588 mg, 8.16 mmol) and acetic acid (374 μL, 6.53 mmol) werediluted in MeOH (21 mL). The reaction mixture was stirred at roomtemperature for 1 hour. Then, sodium cyanoborohydride (410 mg, 6.53mmol) in MeOH (5 mL) was added and the reaction mixture was stirredovernight at room temperature. Then, NaOH 3N (15 mL) was added and themixture was stirred for 1 hour at room temperature. The reaction mixturewas partitioned between water and DCM. The organic layer was dried(MgSO₄), filtered and concentrated. The residue (1 g) was purified bychromatography over silica gel (Irregular SiOH, 15-40 μm; mobile phase100% DCM). The desired fractions were collected and the solvent wasevaporated, yielding 377 mg (55%) of intermediate 38 (colorless oil).

Example A21 Preparation of Intermediate 39

Sodium cyanoborohydride (4.55 g, 72.5 mmol) was added to a solution of3,5-dimethoxyaniline (3.7 g, 24.15 mmol), 1,4-cyclohexanedionemono-ethylene ketal (15 g, 96.6 mmol) and acetic acid (5.5 mL, 96 mmol)in CH₃CN (50 mL) at room temperature (exothermicity observed). Thereaction mixture was stirred overnight. Aqueous NaHCO₃ solution wasadded and the mixture was extracted twice with EtOAc. The combinedorganic layers were washed with brine, dried (MgSO₄), filtered anddried. The residue (21 g) was purified by column chromatography oversilica gel (Irregular SiO₂, 15-40 μm, 90 g; mobile phase gradient from100% DCM to 7% CH₃OH/93% DCM). The pure fractions were collected andevaporated to dryness to give 4.2 g (59%) of intermediate 39.

Example A22 Preparation of Intermediate 42

A solution of 3-bromo-5-methoxy phenol (3.12 g; 15.4 mmol),2-(2-bromoethoxy)tetrahydro-2H-pyran (2.66 mL; 16.9 mmol) and K₂CO₃(1.63 g; 11.8 mmol) was heated at 80° C. in CH₃CN (40 mL) overnight. Thesolution was cooled and the mixture was poured into cooled water, theproduct was extracted with EtOAc, the organic layer was washed with H₂Oand dried (MgSO₄), filtered and evaporated to dryness (5.5 g). Theresidue was purified by chromatography over silica gel (irregular SiOH,15-40 μm, 200 g; mobile phase 80% cyclohexane, 20 EtOAc). The productfractions were collected and the solvent was evaporated, yielding 3.7 g(73%) of intermediate 42.

Example A23 Preparation of Intermediate 43

Sodium hydride (1.03 g, 25.86 mmol) was added portion wise to a solutionof 3-bromo-5-methoxy phenol (3.5 g, 17.24 mmol) in DMF (20 mL) at 5° C.under N₂ flow. The reaction mixture was stirred at 5° C. for 0.5 hour,then a solution of deuteriated-iodomethane (1.29 mL, 20.69 mmol) wasadded dropwise at 5° C. under N₂ flow. The reaction mixture was stirredfor 1 hour at 5° C., then allowed to warm up to room temperature andstirred for 2 hours. The reaction was poured out into ice water, andEtOAc was added. The organic layer was separated, washed with brine,dried (MgSO₄), filtered and the solvent was evaporated to give 4 g ofintermediate 43, used without further purification for the next step.

Example A24 Preparation of Intermediate 44

A solution of 3-bromo-5-methoxyphenol (2 g, 9.85 mmol),1-bromo-2-fluoroethane (1.56 g, 0.012 mol) and K₂CO₃ (1.4 g, 10 mmol)was heated at 80° C. in CH₃CN (30 mL) overnight. The solution was cooledand the mixture was poured into cooled water, the product was extractedwith Et₂O. The organic layer was dried (MgSO₄), filtered and evaporatedto dryness to give 2.27 g of intermediate 44 used without furtherpurification for the next step.

Example A25 Preparation of Intermediate 45

Under N₂ at 10° C., Hunig's base (9.64 mL; 55.16 mmol) was added to asolution of 3-bromo-5-methoxy phenol (5.6 g, 27.58 mmol) in THF (100mL). 2-methoxyethoxymethylchloride (CAS 3970-21-6) (6.3 mL, 55.16 mmol)was added and the solution was stirred at room temperature overnight.The solution was poured into cooled water, and the product was extractedwith EtOAc. The organic layer was dried (MgSO₄), filtered and evaporatedto dryness to give 8 g (99.6%) of intermediate 45 used without furtherpurification for the next step.

Example A26 Preparation of Intermediate 46

A solution of 3-bromo-5-methoxyphenol (0.3 g, 1.5 mmol), 2-iodopropane(0.21 mL, 1.6 mmol) and K₂CO₃ (1.63 g, 12 mmol) was heated at 80° C. inCH₃CN (20 mL) for 24 hours. The solution was cooled and the mixture waspoured into cooled water, the product was extracted with EtOAc. Theorganic layer was washed with H₂O and dried (MgSO₄), filtered andevaporated to dryness to give 350 mg (97%) of intermediate 46 usedwithout further purification for the next step.

Example A26A Preparation of Intermediate 136

NaH (0.74 g; 18.4 mmol) was added portionwise to a solution of(3-chloro-5-methoxyphenyl)methanol (2.9 g; 16.7 mmol) inN,N-dimethylformamide (30 mL) at 5° C. under N₂ flow. The reactionmixture was stirred at 5° C. for 1 hour. Then ethyl iodide (0.96 mL;12.0 mmol) was added dropwise at 5° C. under N₂ flow. The reactionmixture was allowed to warm to room temperature and stirred for 18hours. The reaction was poured out into ice water and EtOAc was added.The organic layer was separated, washed with brine, dried (MgSO₄),filtered and the solvent was evaporated to dryness to give 0.8 g (25%)of intermediate 136.

Example A27 a) Synthesis of Intermediate 66

A mixture of (3-bromopropoxy)-tert-butyldimethylsilane (20 g; 79 mmol)and 2,2,2-trifluoroethylamine (31 mL; 395 mmol) in DMSO (140 mL) washeated at 80° C. for 18 hours. The reaction mixture was cooled to roomtemperature, water was added and the mixture was extracted with Et₂O.The organic layer was dried (MgSO₄), filtered and evaporated tilldryness to provide 19.5 g (91%) of intermediate 66.

b) Synthesis of Intermediate 67

Di-tert-butyl-dicarbonate (7.96; 36.5 mmol), triethylamine (6 mL; 43.11mmol) and N,N-dimethyl-4-aminopyridine (202 mg; 1.7 mmol) were added toa solution of intermediate 66 (9 g; 33.16 mmol) in DCM (90 mL). Thereaction mixture was stirred at room temperature for 2 hours, dilutedwith DCM and water. The organic layer was decanted, washed successivelywith water, a solution of HCl (0.5N) and an aqueous solution of K₂CO₃(10%). The organic layer was dried (MgSO₄), filtered and evaporated tilldryness to provide 11.3 g (92%) of intermediate 67.

c) Synthesis of Intermediate 68

A mixture of intermediate 67 (10.8 g; 29.1 mmol) and tetrabutylammoniumfluoride (34.9 mL of a 1M solution in THF; 34.9 mmol) in THF (80 mL) wasstirred at room temperature overnight. Water was added and the reactionmixture extracted with DCM. The organic layer was dried (MgSO₄),filtered and evaporated till dryness. The residue was purified bychromatography over silica gel (Irregular SiOH, 15-40 μM, 80 g; mobilephase, gradient from 99% DCM, 1% MeOH to 96% DCM, 4% MeOH). The purefractions were collected and evaporated till dryness to provide 3.65 g(49%) of intermediate 68.

d) Synthesis of Intermediate 69

Methane sulfonyl chloride (431 μL; 5.8 mmol) was added dropwise to asolution of intermediate 68 (Ig; 3.9 mmol) and triethylamine (811 μL;5.8 mmol) in DCM (15 mL) at 5° C. under N₂ flow. The reaction mixturewas stirred for 30 minutes at room temperature. The reaction mixture wasevaporated till dryness and the resulting intermediate 69 was usedwithout further purification for the next step.

Example A28 a) Preparation of Intermediate 70

The experiment has been performed 5 times on the following amount.

NaH (0.25 g; 5.4 mmol) was added portionwise to a solution of2-amino-2-methyl-1-propanol (1.54 mL; 16.1 mmol) inN,N-dimethylformamide (12 mL) at 5° C. under N₂ flow. The reactionmixture was stirred at 5° C. for 15 minutes. Then, compound 76 (1.4 g;3.35 mmol) was added dropwise at 5° C. under N₂ flow. The reactionmixture was allowed to warm to room temperature and stirred overnight.The reaction was poured out into ice water and EtOAc was added. Theorganic layer was separated, washed with brine, dried (MgSO₄), filteredand the solvent was evaporated to dryness to give 10.5 g of a residuewhich was purified by chromatography over silica gel (Irregular SiOH,15-40 μm, 300 g; mobile phase 1% NH₄OH, 90% DCM, 10% MeOH). The purefractions were collected and concentrated yielding 3.6 g (42%) ofintermediate 70.

b) Preparation of Intermediate 71

Di-tert-butyl dicarbonate (0.24 g; 1.1 mmol) was added to a solution ofintermediate 70 (0.62 g; 1.1 mmol) and NaHCO₃(0.19 g; 2.3 mmol) indioxane (15 mL) and water (15 mL). The mixture was stirred at roomtemperature for 18 hours. The reaction mixture was poured out into icewater and DCM was added. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated to dryness. The residue (0.8 g)was purified by chromatography over silica gel (SiOH, 5 μm 150*30 mm;mobile phase 0.2% NH₄OH, 98% DCM, 2% MeOH). The pure fractions werecollected and the solvent was evaporated to give 0.59 g (85%) ofintermediate 71.

c) Preparation of Intermediate 72

Methanesulfonyl chloride (0.96 mL; 12.4 mmol) was added dropwise to asolution of intermediate 71 (2.7 g, 4.45 mmol) and triethylamine (1.86mL; 13.35 mmol) in DCM (25 mL) at 5° C. under a N₂ flow. The reactionmixture was stirred for 18 hours allowing the temperature to rise toroom temperature. The reaction mixture was poured out into ice water andDCM was added. The organic layer was separated, dried (MgSO₄), filteredand the solvent was evaporated to dryness. The residue (4.1 g) waspurified by chromatography over silica gel (Irregular SiOH, 20-45 μm,450 g; mobile phase 0.2% NH₄OH, 97% DCM, 3% MeOH). The pure fractionswere collected and the solvent was evaporated to give 3 g (100%) ofintermediate 72.

d) Preparation of Intermediate 73

Trifluoroacetic acid (0.97 mL; 13.1 mmol) was added to a solution ofintermediate 72 (0.6 g; 0.87 mmol) in DCM (12.5 mL) at 0° C. Thereaction was stirred at room temperature for 1 hour. The mixture waspoured out into ice water and DCM was added. The mixture was basifiedwith a solution of NaHCO₃ and the organic layer was separated, driedover MgSO₄, filtered and the solvent was evaporated to give 597 mg ofintermediate 73 used without further purification for the next step.

Example A29 Preparation of Intermediate 74

Methanesulfonyl chloride (3.32 mL; 42.9 mmol) was added dropwise to asolution of compound 606 (6 g; 14.3 mmol) and triethylamine (10 mL; 71.5mmol) in DCM (240 mL) at 5° C. under a N₂ flow. The reaction mixture wasstirred for 1 hour at 5° C. and allowed to rise to room temperature for1 hour. The reaction mixture was poured out into ice water and DCM wasadded. The organic layer was separated, dried (MgSO₄), filtered and thesolvent was evaporated to dryness to give 9.6 g of intermediate 74 usedwithout further purification for the next step

Example A30 a) Preparation of Intermediate 75

NaH (11.4 g; 82.5 mmol) was added portionwise to a solution of4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (4 g; 20.6mmol) in acetone (60 mL) at 5° C. under N₂ flow. The reaction mixturewas stirred at 5° C. for 15 minutes. Then, acetamide, 2-bromo-N-methyl(6.3 g; 41.3 mmol) was added dropwise at 5° C. under N₂ flow. Thereaction mixture was stirred at 65° C. for 24 hours. The reactionmixture was cooled to room temperature. The precipitate was filtered offand washed with DCM. The filtrate was evaporated till dryness, taken upinto DIPE/diethyl ether and stirred at room temperature for 15 minutes.The precipitate was filtered off and washed with DCM. The filtrate wasevaporated till dryness to afford 9 g of intermediate 75 used withoutfurther purification for the next step.

b) Preparation of Intermediate 76

A mixture of intermediate 14 (5.7 g; 11.7 mmol), intermediate 75(N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-acetamide)(6.2 g; 23.5 mmol), potassium phosphate (7.5 g; 35.2 mmol) anddicyclohexyl(2′,6′-dimethoxy[1,1′-biphenyl]-2-yl)phosphine (0.482 g; 1.2mmol) in dioxane (140 mL) and H₂O (60 mL) was stirred at roomtemperature under N₂ flow. After 10 minutes, Pd₂(dba)₃ (1 g; 1.2 mmol)was added portionwise at room temperature under N₂ flow. The reactionmixture was heated at 80° C. for 4 hours. The reaction mixture wascooled to room temperature and poured out into ice water. The mixturewas filtered over a pad of Celite®, washed with DCM. The organic layerwas washed with brine, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (8.3 g) was purified by chromatography oversilica gel (Irregular SiOH, 20-40 μm, 450 g; mobile phase 0.1% NH₄OH,98% DCM, 2% MeOH). The pure fractions were collected and concentrated togive 3.5 g (51%) of intermediate 76.

Example A31 Preparation of Intermediate 77

Methanesulfonyl chloride (0.73 mL; 9.4 mmol) was added dropwise to asolution of compound 614(1.5 g; 3.15 mmol) and triethylamine (2.2 mL;15.7 mmol) in DCM (40 mL) at 5° C. under a N₂ flow. The reaction mixturewas stirred for 1 hour at 5° C. and allowed the temperature to rise toroom temperature for 1 hour. The reaction mixture was poured out intoice water and DCM was added. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated to dryness to give 2.5g of intermediate 77 used without further purification for the nextstep.

Example A32 a) Preparation of Intermediate 78

NaH (0.44 g; 10.9 mmol) was added portionwise to a solution of7-bromo-2-(1H-pyrazol-4-yl)quinoxaline (1.5 g; 5.45 mmol) inN,N-dimethylformamide (40 mL) at 0° C. under N₂ flow. The reactionmixture was stirred at 5° C. for 15 minutes. Then, carbamic acid,N-(3-bromopropyl)-1,1-dimethylethyl ester (2.6 g; 10.9 mmol) was addeddropwise at 5° C. under N₂ flow. The reaction mixture was stirred atroom temperature for 18 hours. The reaction mixture was poured out intoice water, EtOAc was added. The organic layer was separated, washed withwater, diethyl ether, dried (MgSO₄), filtered and evaporated to afford1.3 g of intermediate 78 used without further purification for the nextstep.

b) Preparation of Intermediate 79

Under an inert atmosphere, a solution of palladium acetate (0.11 g; 0.48mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (0.3 g; 0.48mmol)) was added to room temperature to a solution of intermediate 41(3.3 g; 10.6 mmol), intermediate 78 (4.2 g; 9.63 mmol) and cesiumcarbonate (3.8 g; 11.6 mmol) in dimethoxyethane (50 mL). The reactionmixture was stirred at 85° C. for 3 days. The reaction mixture wascooled to room temperature and poured out into ice water, K₂CO₃ 10% andEtOAc was added. The mixture was filtered over a pad of Celite®. Theorganic layer was washed with brine, dried (MgSO₄), filtered and thesolvent was evaporated. The residue (8.5 g) was purified bychromatography over silica gel (Irregular SiOH, 20-40 μm, 450 g; mobilephase 0.1% NH₄OH, 97% DCM, 3% MeOH). The pure fractions were collectedand concentrated to give 3.3 g (52%) of intermediate 79.

c) Preparation of Intermediate 80

A 1M solution of tetrabutylammonium fluoride in THF (5.5 mL; 5.5 mmol)was added dropwise to a solution of intermediate 79 (3.3 g; 5 mmol) inTHF (60 mL) at room temperature. The reaction mixture was stirred atroom temperature for 3 hours. The mixture was poured out into ice waterand EtOAc was added. The mixture was basified with K₂CO₃ 10% and theorganic layer was separated, washed with brine, dried (MgSO₄), filteredand the solvent was evaporated to dryness. The residue was crystallizedfrom diethyl ether/CH₃CN. The precipitate was filtered off, dried invacuum to provide 2 g (73%) of intermediate 80.

d) Preparation of Intermediate 81

Methanesulfonyl chloride (0.85 mL; 10.9 mmol) was added dropwise to asolution of intermediate 80 (2 g; 3.65 mmol) and triethylamine (2.54 mL;18.2 mmol) in DCM (50 mL) at 5° C. under a N₂ flow. The reaction mixturewas stirred for 1 hour at 5° C. and allowed the temperature to rise toroom temperature for 2 hours. The reaction mixture was poured out intoice water and DCM was added. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated to dryness to give 2.5g of intermediate 81 used without further purification for the nextstep.

e) Preparation of Intermediate 82

A mixture of intermediate 81 (2.5 g; 4 mmol) and isopropylamine (5.2 mL;59.9 mmol) in acetonitrile (25 mL) was heated at 100° C. in a sealedvessel for 18 hours. The reaction mixture was cooled to roomtemperature. The reaction mixture was poured out into ice water, EtOAcwas added. The organic layer was separated, washed with a solution ofNaHCO₃, dried (MgSO₄), filtered and evaporated till dryness. The residue(3 g) was purified by chromatography over silica gel (Irregular SiOH,20-40 μm, 450 g; mobile phase from 0.1% NH₄OH, 95% DCM, 5% MeOH). Thepure fractions were collected and concentrated to give 1.1 g (47%) ofintermediate 82.

Example A33 a) Preparation of Intermediate 83

A mixture of 5-bromo-benzene-1,3-diol (7.3 g; 38.6 mmol), cesiumcarbonate (37.75 g; 115.9 mmol) and iodomethane-D3 (4.8 mL; 77.25 mmol)in CH₃CN (150 mL) was stirred at 80° C. for 18 hours. The reactionmixture was cooled to room temperature and poured out into ice water andEtOAc was added. The organic layer was washed with brine, dried (MgSO₄),filtered and the solvent was evaporated to afford 5.3 g of intermediate83 used without further purification for the next step.

b) Preparation of Intermediate 84

Under an inert atmosphere, a solution of palladium acetate (0.21 g; 0.9mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (0.57 g; 0.9mmol) was added to room temperature to a solution of intermediate 5 (2g; 10.6 mmol), intermediate 83 (2.45 g; 11 mmol) and sodium tertbutoxide (2.64 g; 27.4 mmol) in dioxane (150 mL). The reaction mixturewas stirred at 100° C. for 4 days. The reaction mixture was cooled toroom temperature and poured out into ice water and EtOAc was added. Themixture was filtered over a pad of Celite®. The organic layer was washedwith brine, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (6 g) was purified by chromatography over silica gel (IrregularSiOH, 15-40 μm, 300 g; mobile phase 0.1% NH₄OH, 97% DCM, 3% MeOH). Thepure fractions were collected and concentrated. The residue (4 g) wascrystallized from diethyl ether. The precipitate was filtered off, driedin vacuum to provide 3.6 g (90%) of intermediate 84. MP: 198° C. (DSC)

c) Preparation of Intermediate 85

NaH (0.107 g; 2.69 mmol) was added portionwise to intermediate 84 (0.49g; 1.35 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture wasstirred at 5° C. for 1 hour. Then, a solution of deuterated(2-bromoethoxy)(1,1-dimethylethyl)dimethyl-silane (deuterated version ofCAS 86864-60-0; prepared by art-known deuteration method) (0.65 g; 2.7mmol) was added dropwise at 5° C. under N₂ flow. The reaction mixtureallowed to warm to room temperature and stirred for 4 hours. Thereaction was poured out into ice water and EtOAc was added. The organiclayer was separated and washed with brine, dried (MgSO₄), filtered andthe solvent was evaporated to afford 0.88 g of intermediate 85 usedwithout further purification for the next step.

Example A34 Preparation of Intermediate 86

Methanesulfonyl chloride (0.17 mL, 2.1 mmol) was added dropwise to asolution of compound 617 (0.294 g, 0.7 mmol) and triethylamine (0.49 mL,3.5 mmol) in DCM (5 mL) at 5° C. under a N₂ flow. The reaction mixturewas stirred for 1 hour at 5° C. and allowed the temperature to rise toroom temperature for 1 hour. The reaction mixture was poured out intoice water and DCM was added. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated to dryness to give 0.45g of intermediate 86 used without further purification for the nextstep.

Example A35 Preparation of Intermediate 87

A mixture of compound 4 (1.3 g; 2.9 mmol), N-(3-bromopropyl) phtalimide(1.56 g; 5.8 mmol) and K₂CO₃ (0.805 g; 5.8 mmol) in CH₃CN (100 mL) wasstirred at 80° C. for 48 hours. The reaction mixture was cooled to roomtemperature, poured out into ice water and EtOAc was added. The organiclayer was separated, washed with brine, dried (MgSO₄), filtered and thesolvent was evaporated until dryness. The residue (0.566 g) was purifiedby chromatography over silica gel (SiOH, 15-40 μm, 50 g; mobile phase0.1% NH₄OH, 96% DCM, 4% MeOH). The product fractions were collected andthe solvent was evaporated to give 1.26 g (34%) of intermediate 87.

Example A36A Preparation of Intermediate 88

A mixture of intermediate 88b

(see A4c-2) (0.53 g; 1.1 mmol),1,3,5-trimethyl-4-(tributylstannyl)-1H-Pyrazole (Synthesis, (13),1949-1958; 2001) (1.33 g; 3.33 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.064 g; 0.055 mmol) intoluene (3 mL) was stirred at 160° C. for 40 minutes using one singlemode microwave (Biotage). The reaction mixture was cooled to roomtemperature and evaporated till dryness. The residue was purified bychromatography over silica gel (Irregular SiOH, 40 μm; mobile phasegradient from 90% DCM, 10% Heptane to 100% DCM, then 99% DCM 1% MeOH).The pure fractions were collected and concentrated to give 0.41 g (68%)of intermediate 88.

Intermediate 88b

solution of tetrabutylammonium fluoride (3.016 mmol; 3.016 ml) dropwiseto a solution of intermediate 88b (2.742 mmol; 1.30 g) in THF (25 ml).The reaction mixture was stirred at room temperature overnight. Thereaction mixture was poured out into ice water, EtOAc was added and theorganic layer was separated, washed with brine, dried (MgSO₄), filteredand the solvent was evaporated. The residue was purified by columnchromatography over silica gel (SiO₂=30 g-15/40 μm) Eluent: CH₂Cl₂ 100to CH₂Cl₂ 98/MeOH 2, yielding intermediate 88a.

Alternative pyrazole derivatives which can be used in the above protocolcan be prepared as follows:

A) a) Preparation of Intermediate 125

N-butyllithium 1.6M in hexane (33.5 mL; 53.6 mmol) was added dropwise toa solution of 1-methylpyrazole (4 g; 48.8 mmol) in THF (66 mL) at −78°C. under N₂ flow. The reaction mixture was stirred at 0° C., then(2-bromoethoxy)-tert-butyldimethylsilane (12.5 mL; 58.5 mmol) was addedto the solution at −78° C. and was stirred for 1 hour. The temperatureof the reaction mixture was allowed to rise to room temperature andstirred for 18 hours. The reaction mixture was poured out into ice waterand EtOAc was added. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue (16 g) was purifiedby chromatography over silica gel (Irregular SiOH, 20-45 μm, 1000 g;mobile phase 65% Heptane, 35% EtOAc). The pure fractions were collectedand concentrated to give 3 g (25%) of intermediate 125.

b) Preparation of Intermediate 126

Pyridinium bromide perbromide 95% (3.5 g; 10.8 mmol) was added to asolution of intermediate 125 (2.6 g; 10.8 mmol) in MeOH (130 mL). Thereaction mixture was stirred at 0° C. for 1 hour and room temperaturefor 18 hours. The solvent was evaporated and the residue was poured outinto water and K₂CO₃ 10%. DCM was added and the organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated todryness. The residue (2.5 g) was purified by chromatography over silicagel (Irregular SiOH, 20-40 μm, 300 g; mobile phase 0.1% NH₄OH, 97% DCM,3% MeOH). The pure fractions were collected and concentrated to give 2 g(92%) of intermediate 126.

c) Preparation of Intermediate 127

Tert-butyldimethylsilyl chloride (1.9 g; 12.7 mmol), imidazole (1.6 g;23.4 mmol) were successively added to a solution of intermediate 126 (2g; 9.75 mmol) in N,N-dimethylformamide (7 mL). The reaction mixture wasstirred at room temperature for 18 hours. The reaction mixture wasquenched with water and extracted with Et₂O. The organic layer wasdecanted, washed with water, then brine, dried (MgSO₄), filtered andevaporated to dryness. The residue was purified by chromatography oversilica gel (SiOH, 10-40 μm, 90 g; mobile phase from 100% DCM to 97% DCM,3% MeOH). The pure fractions were collected and concentrated to give 2.8g (90%) of intermediate 127.

d) Preparation of Intermediate 128

N-butyllithium 1.6M in hexane (0.22 mL; 0.35 mmol) was added dropwise toa solution of intermediate 127 (0.102 g; 0.32 mmol) in Et₂O (1.5 mL) at−78° C. under N₂ flow. The reaction mixture was stirred for 30 minutes,then tributyltin chloride (0.095 mL; 0.35 mmol) was added to thesolution and was stirred at room temperature for 18 hours. The reactionmixture was poured out into ice water and Et₂O was added. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated to dryness. The residue (0.160 g) was purified bychromatography over silica gel (Spherical SiOH, 10 μm, 60 g; mobilephase 80% Heptane, 20% EtOAc). The pure fractions were collected andconcentrated to give 0.055 g (32%) of intermediate 128.

B) a) Preparation of Intermediate 129

N-butyllithium 1.6M in hexane (25 mL; 40.2 mmol) was added dropwise to asolution of 1-methylpyrazole (3 mL; 35.5 mmol) in THF (50 mL) at −78° C.under N₂ flow. The reaction mixture was stirred at 0° C., thenEschenmoser's salt (8.1 g; 43.85 mmol) was added to the solution at −78°C. and was stirred for 1 hour. The temperature of the reaction mixturewas allowed to rise to room temperature and stirred for 18 hours. Thereaction mixture was poured out into ice water and EtOAc was added. Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated to afford 3.1 g of intermediate 129.

b) Preparation of Intermediate 130

Pyridinium bromide perbromide 95% (6.9 g; 21.6 mmol) was added to asolution of intermediate 130 (3 g; 21.6 mmol) in MeOH (200 mL). Thereaction mixture was stirred at 0° C. for 1 hour and room temperaturefor 18 hours. The solvent was evaporated and the residue was poured outinto water and K₂CO₃ 10%. DCM was added and the organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated todryness. The residue (3.1 g) was purified by chromatography over silicagel (Irregular SiOH, 20-40 μm, 450 g; mobile phase 0.1% NH₄OH, 97% DCM,3% MeOH). The pure fractions were collected and concentrated to give1.35 g (29%) of intermediate 130.

c) Preparation of Intermediate 131

N-butyllithium 1.6M in hexane (0.8 mL; 1.26 mmol) was added dropwise toa solution of intermediate 130 (0.25 g; 1.15 mmol) in Et₂O/THF (1/2) (3mL) at −78° C. under N₂ flow. The reaction mixture was stirred for 30minutes. Then tributyltin chloride (1.58 mL; 5.8 mmol) was added to thesolution and was stirred at room temperature for 18 hours. The reactionmixture was poured out into ice water and Et₂O was added. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated to dryness to give 0.52 g of intermediate 131 used withoutfurther purification for the next step.

Example A36B Preparation of Intermediate 89

Methanesulfonyl chloride (0.066 mL; 0.85 mmol) was added dropwise to asolution of compound 622 (0.185 g; 0.43 mmol), triethylamine (0.14 mL;0.98 mmol) and 4-dimethylaminopyridine (0.005 g; 0.043 mmol) in THF (5mL) at 5° C. under a N₂ flow. The temperature of the reaction mixturewas allowed to rise to room temperature for 2 hours.

The reaction mixture was poured out into ice water and DCM was added.The organic layer was separated, dried (MgSO₄), filtered and the solventwas evaporated to dryness to give 0.26 g (yellow oil) of intermediate 89used without further purification for the next step.

Example A37 Preparation of Intermediate 91

Methanesulfonyl chloride (1 mL; 12.8 mmol) was added dropwise to asolution of 1-piperidinecarboxylic acid, 4-(3-hydroxy-1-propyn-1-yl)-,1,1-dimethylethyl ester (2 g; 8.5 mmol), triethylamine (1.8 mL; 12.8mmol) and 4-dimethylaminopyridine (10.4 g; 85 mmol) in DCM (20 mL) at 5°C. under a N₂ flow. The temperature pof the reaction mixture was allowedto rise to room temperature for 18 hours. The reaction mixture waspoured out into ice water and DCM was added. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated todryness to give 1.41 g of intermediate 91 used without furtherpurification for the next step.

Example A38 Preparation of Intermediate 92

NaH (0.24 g; 6.0 mmol) was added portionwise to intermediate 3 (1 g; 3.0mmol) in N, N-dimethylformamide (30 mL). The reaction mixture wasstirred at 10° C. for 1 hour. Then 2-butyn-1-ol,4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-, 1-methanesulfonate (4.2 g;15.0 mmol) was added dropwise under N₂ flow. The reaction mixture wasstirred at room temperature for 18 hours. The reaction was poured outinto ice water and EtOAc was added. The organic layer was separated andwashed with brine, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (4.2 g) was purified by chromatography oversilica gel (Irregular SiOH 15-40 μm, 300 g; mobile phase 60% Heptane, 4%MeOH, 36% EtOAc). The pure fractions were collected and concentrated togive 0.185 g (11%) of intermediate 92.

Example A39 Preparation of Intermediate 93

Methanesulfonyl chloride (9.9 mL; 127.7 mmol) was added dropwise to asolution of compound 2 (10 g; 25.55 mmol), triethylamine (24.9 mL; 178.8mmol) in DCM (400 mL) at 5° C. under a N₂ flow. The reaction mixture wasstirred at room temperature for 2 hours. The reaction mixture was pouredout into ice water and DCM was added. The organic layer was separated,dried (MgSO₄), filtered and the solvent was evaporated to dryness togive 17.6 g of intermediate 93 used without further purification for thenext step.

Example A40 Preparation of Intermediate 94

(see A4c-2)(9.5 g; 20 mmol),4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (4.3 g; 22mmol), potassium phosphate (8.5 g; 40 mmol) in dioxane (1 L) and water(120 mL) were degassed with N₂ for 15 minutes, then S-Phos (0.83 g; 2mmol) and Pd₂(dba)₃ (7.6 g; 6.6 mmol) was added. The reaction mixturewas heated at 80° C. for 15 hours. The reaction mixture was cooled toroom temperature. The reaction mixture was poured out into ice water,EtOAc was added and was filtered off on a pad of Celite®. The organiclayer was separated, washed with brine, dried (MgSO₄), filtered andevaporated till dryness. The residue (18.5 g) was purified bychromatography over silica gel (Irregular SiOH 20-45 μm, 1000 g; mobilephase 96% DCM, 4% MeOH). The pure fractions were collected andconcentrated to give 5.1 g (51%) of intermediate 94.

Example A41 a) Preparation of Intermediate 95

NaH (0.2 g; 4.75 mmol) was added portionwise to intermediate 94 (2 g; 4mmol) in N,N-dimethylformamide (30 mL). The reaction mixture was stirredat 10° C. for 1 hour. Then 1-bromo-3-chloropropane (0.5 mL; 4.75 mmol)was added dropwise under N₂ flow. The reaction mixture was stirred atroom temperature for 1 hour. The reaction was poured out into ice waterand EtOAc was added. The organic layer was separated and washed withbrine, dried (MgSO₄), filtered and the solvent was evaporated to afford2.5 g of intermediate 95 used without further purification for the nextstep.

b) Preparation of Intermediate 96

A mixture of intermediate 95 (1.1 g; 1.48 mmol),1-(2-hydroxylethyl)piperazine (0.407 g; 2.95 mmol), K₂CO₃ (1.92 g; 14.74mmol) in CH₃CN (10 mL) was stirred at 90° C. for 12 hours. The reactionmixture was poured out into ice water and EtOAc was added. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated to dryness to give 0.9 g of intermediate 96 used withoutfurther purification for the next step.

c) Preparation of Intermediate 97

A mixture of intermediate 96 (0.56 g; 0.83 mmol), acetyl chloride (0.12mL; 1.66 mmol), triethylamine (0.27 mL; 1.9 mmol) and4-dimethylaminopyridine (0.01 g; 0.083 mmol) was stirred in DCM (10 mL)at 5° C. under a N₂ flow. The reaction mixture was stirred to roomtemperature for 18 hours. The reaction mixture was poured out into icewater and DCM was added. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated to dryness to give 0.85 g ofintermediate 97 used without further purification for the next step.

d) Preparation of Intermediate 98

A 1M solution of tetrabutylammonium fluoride in THF (2.5 mL, 2.5 mmol)was added dropwise to a solution of intermediate 97, (0.75 g, 0.84 mmol)in THF (5 mL) at room temperature. The reaction mixture was stirred atroom temperature for 3 hours. The mixture was poured out into ice water,basified with K₂CO₃ 10% and EtOAc was added. The organic layer wasseparated, washed with brine, dried (MgSO₄), filtered and the solventwas evaporated to dryness. DCM and a few MeOH were added, then theinsoluble fraction was filtered off and the filtrate was evaporated. Theresidue and the precipitate were combined and dissolved in DCM. Theorganic layer was washed with water, dried (MgSO₄), filtered and thesolvent was evaporated to dryness. The residue (0.5 g) was purified bychromatography over silica gel (SiOH, 15-40 μm, 90 g; mobile phase from0.3% NH₄OH, 97% DCM, 3% MeOH to 1% NH₄OH, 90% DCM, 10% MeOH). The purefractions were collected and concentrated to give 0.238 g (47%) ofintermediate 98.

e) Preparation of Intermediate 99

Methanesulfonyl chloride (0.1 mL; 1.3 mmol) was added dropwise to asolution of intermediate 98 (0.19 g; 0.26 mmol) and triethylamine (0.11mL; 0.78 mmol) in DCM (5 mL) at 5° C. under a N₂ flow. The reactionmixture was stirred at 10° C. for 2 hours. The reaction mixture waspoured out into ice water and DCM was added. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated todryness to give 0.51 g of intermediate 99-AAA used without furtherpurification for the next step.

f) Preparation of Intermediate 100

A mixture of intermediate 99 (0.51 g; 0.26 mmol) and isopropylamine (5.9mL; 68.9 mmol) in acetonitrile (1 mL) was heated at 100° C. in a sealedvessel for 12 hours. The reaction mixture was cooled to roomtemperature. The reaction mixture was poured out into ice water, DCM wasadded. The organic layer was separated, washed, dried (MgSO₄), filteredand evaporated till dryness. The residue (0.59 g) was purified bychromatography over silica gel (Irregular SiOH, 15-40 μm, 30 g; mobilephase 0.7% NH₄OH, 93% DCM, 7% MeOH). The pure fractions were collectedand concentrated to give 0.09 g (54%) of intermediate 100.

Example A42 a) Preparation of Intermediate 101

A mixture of intermediate 5 (3 g; 13.3 mmol), intermediate 45 (3.9 g;13.3 mmol), sodium tert-butoxide (3.9 g; 40 mmol) and1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine (0.83 g;1.33 mmol) in ethylene glycol dimethyl ether (100 mL) was degassed withN₂ for 10 minutes. Palladium(II) acetate (0.3 g; 1.33 mmol) was addedand the mixture was stirred at 90° C. for 2 hours. The mixture wascooled down to room temperature, poured into H₂O and DCM. The mixturewas filtered off on a pad of Celite®. The filtrate was extracted withDCM. The combined organic layers were dried (MgSO₄), filtered andevaporated to dryness to give 5 g of crude compound. The residue waspurified by chromatography over silica gel (SiOH, 20-45 μm, 40 g; Mobilephase 0.1% NH₄OH, 97% DCM, 3% MeOH). The pure fractions were collectedand the solvent was evaporated, yielding 3.6 g (62%) of intermediate101.

b) Preparation of Intermediate 102

NaH (0.37 g; 9.2 mmol) was added portionwise to a solution ofintermediate 101 (2 g; 4.6 mmol) in N,N-dimethylformamide (20 mL) at 5°C. under N₂ flow. The reaction mixture was stirred at 5° C. for 30minutes. Then (2-bromoethoxy)-tert-butyldimethylsilane (1.3 mL; 6.0mmol) was added dropwise at 5° C. under N₂ flow. The reaction mixturewas stirred for 15 hours at room temperature. The reaction was pouredout into ice water and EtOAc was added. The organic layer was separated,washed with brine, dried (MgSO₄), filtered and the solvent wasevaporated to dryness to give 3 g of intermediate 102.

c) Preparation of Intermediate 103

A 1M solution of tetrabutylammonium fluoride in THF (5 mL; 5 mmol) wasadded dropwise to a solution of intermediate 102 (3 g; 5 mmol) in THF(50 mL) at room temperature. The reaction mixture was stirred at roomtemperature for 15 hours. The mixture was poured out into ice water,basified with K₂CO₃ 10% and EtOAc was added. The organic layer wasseparated, washed with brine, dried (MgSO₄) and the solvent wasevaporated to dryness. The residue (3 g) was purified by chromatographyover silica gel (SiOH, 15-40 μm, 40 g; mobile phase 0.1% NH₄OH, 95% DCM,5% MeOH). The pure fractions were collected and concentrated to give 2.2g (61%) of intermediate 103.

d) Preparation of Intermediate 104

Methanesulfonyl chloride (0.7 mL; 9.2 mmol) was added dropwise to asolution of intermediate 103 (2.2 g; 4.6 mmol), triethylamine (1.6 mL;11.5 mmol) in DCM (30 mL) at 5° C. under a N₂ flow. The reaction mixturewas stirred at 10° C. for 2 hours. The reaction mixture was poured outinto ice water and DCM was added. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated to dryness to give 2.8g of intermediate 104 used without further purification for the nextstep.

e) Preparation of Intermediate 105

A mixture of intermediate 104 (2 g; 3.6 mmol) and 2-propanamine (1.6 mL;17.9 mmol) in acetonitrile (15 mL) was heated at 100° C. in a sealedvessel for 18 hours. The reaction mixture was cooled to roomtemperature. The reaction mixture was poured out into ice water, EtOAcwas added. The organic layer was separated, washed with bine, dried(MgSO₄), filtered and evaporated till dryness. The residue (2.2 g) waspurified by chromatography over silica gel (SiOH, 15-40 μm, 40 g; mobilephase 0.1% NH₄OH, 95% DCM, 5% MeOH). The pure fractions were collectedand concentrated to give 0.8 g (43%) of intermediate 105.

Example A43 Preparation of Intermediate 107

Methanesulfonyl chloride (0.19 mL; 2.4 mmol) was added dropwise to asolution of compound 625 (0.69 g; 1.2 mmol) (prepared according to theprocedure described in B39 starting from

which is prepared according to the procedure described in A2c) startingfrom intermediate 41 and intermediate 106), triethylamine (0.4 mL; 3mmol) in DCM (10 mL) at 5° C. under a N₂ flow. The reaction mixture wasstirred at room temperature for 3 hours. The reaction mixture was pouredout into ice water and DCM was added. The organic layer was separated,dried (MgSO₄), filtered and the solvent was evaporated to dryness togive 0.8 g of intermediate 107 as an orange oil used without furtherpurification for the next step.

Intermediate 107 was converted into compound 650 according to theprocedure described in B3 (first alternative protocol).

Example A43A Preparation of Intermediate 106

NaH (0.3 g; 7.2 mmol) was added portionwise to a solution of7-bromo-2-(1H-pyrazol-4-yl)quinoxaline (1.6 g; 6 mmol) inN,N-dimethylformamide (100 mL) at 5° C. under N₂ flow. The reactionmixture was stirred at 5° C. for 1 hour. Then4-methylsulfonyloxy-1-piperidinecarboxylate CAS [141699-59-4](3.5 g;12.6 mmol) was added dropwise at 5° C. under N₂ flow. The reactionmixture was stirred for 18 hours at 100° C. The reaction was poured outinto ice water and EtOAc was added. The organic layer was separated,washed with brine, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (8.4 g) was purified by chromatography oversilica gel (Irregular, SiOH, 20-40 μm; 450 g; mobile phase 0.1% NH₄OH,98% DCM, 2% MeOH). The pure fractions were collected and concentrated togive 3.7 g (67%) of intermediate 106 (yellow oil).

Example A44 Preparation of Intermediate 109

NaH (0.29 g; 7.4 mmol) was added portionwise to intermediate 108

(1.5 g; 3.7 mmol) (prepared according to the procedure described inA33b) in N,N-dimethylformamide (25 mL). The reaction mixture was stirredat 0° C. for 30 minutes. Then 3-bromo-(1-trimethylsilyl)-1-propyne (1.6mL; 10.2 mmol) was added dropwise at 5° C. under N₂ flow. The reactionmixture was stirred at 5° C. for 1 hour. The reaction was poured outinto ice water and EtOAc was added. The organic layer was separated andwashed with brine, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (2 g) was purified by chromatography over silicagel (SiOH 15-40 μm, 80 g mobile phase 98% DCM, 2% MeOH) to give 1.4 g ofintermediate 109.

Example A45 Preparation of Intermediate 110

A mixture of compound 4 (0.5 g; 1.2 mmol), 4-nitrobenzyl bromide (0.29g; 1.35 mmol) and K₂CO₃ (0.24 g; 51.8 mmol) in CH₃CN (20 mL) was stirredat room temperature for 48 hours. The reaction mixture was cooled toroom temperature, poured out into ice water and EtOAc was added. Theorganic layer was separated, washed with brine, dried (MgSO₄), filteredand the solvent was evaporated until dryness. The residue (0.8 g) waspurified by chromatography over silica gel (Stability SiOH, 5 μm, 150*30mm; mobile phase gradient from 71% Heptane, 1% MeOH, 28% EtOAc to 20%MeOH, 80% EtOAc). The product fractions were collected and the solventwas evaporated to give 0.34 g (52%) of intermediate 110.

Example A46 a) Preparation of Intermediate 113

NaH (0.52 g; 13 mmol) was added portionwise to7-bromo-2-(1H-pyrazolyl-4-yl)quinoxaline (3 g; 11 mmol) inN,N-dimethylformamide (30 mL). The reaction mixture was stirred at 5° C.for 1 hour. Then 4-bromomethyltetrahydropyran (2.4 mL; 13 mmol) wasadded dropwise at 5° C. under N₂ flow. The reaction mixture was stirredat 5° C. for 1 hour, then was allowed to room temperature and stirredfor 18 hours. The reaction was poured out into ice water and EtOAc wasadded. The organic layer was separated and washed with brine, dried(MgSO₄), filtered and the solvent was evaporated. The residue wascrystallized from DIPE and CH₃CN. The precipitate was filtered and driedto give 2.6 g (64%) of intermediate 113.

b) Preparation of Intermediate 112

Under an inert atmosphere, a solution of palladium acetate (0.08 g; 0.35mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (0.22 g; 0.35mmol) was added to room temperature to a solution of intermediate 113(2.6 g; 7.0 mmol), 3,5-dimethoxyaniline (1 g; 7.0 mmol) and sodium tertbutoxide (2 g; 21 mmol) in dioxane (40 mL). The reaction mixture wasstirred at 90° C. for 18 hours. The reaction mixture was cooled to roomtemperature and poured out into ice water and DCM was added. The mixturewas filtered over a pad of Celite®. The organic layer was washed withwater, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (3.5 g) was purified by chromatography over silica gel (SiOH,15-40 μm, mobile phase 98% DCM, 2% MeOH). The pure fractions werecollected and concentrated to give 1.6 g (63%) of intermediate 112.

Example A47 a) Preparation of Intermediate 114

Intermediate 13 (9 g; 28.5 mmol), intermediate 132 (20.9 g; 57 mmol),potassium phosphate (12.1 g; 57 mmol) in dioxane (200 mL) and water (80mL) were degassed with N₂ for 15 minutes, then S-Phos (1.2 g; 2.9 mmol)and Pd₂(dba)₃ (1.3 g, 1.4 mmol) weres added. The reaction mixture washeated at 80° C. for 6 hours. The reaction mixture was cooled to roomtemperature. The reaction mixture was poured out into ice water, EtOAcwas added and was filtered off on a pad of Celite®. The organic layerwas separated, washed with brine, dried (MgSO₄), filtered and evaporatedtill dryness. The residue (28 g) was purified by chromatography oversilica gel (Irregular SiOH 20-45 μm, 1000 g; mobile phase 99% DCM, 1%MeOH). The pure fractions were collected and concentrated to give 13.6 g(92%) of intermediate 114.

Intermediate 132

was prepared as follows:

NaH (77.3 mmol; 3 g) was added to a solution of 4,4,5,5tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (10 g; 51.5 mmol) inN,N-dimethylformamide (150 mL) at room temperature under N₂ flow. Thereaction was stirred at room temperature for 1 hour. Then a solution of(3-bromopropoxy)-tert-butyldimethylsilane (18.5 mL; 77.3 mmol) was addeddropwise at room temperature under N₂ flow. The reaction mixture wasstirred at room temperature overnight. The reaction mixture was pouredout into ice water and EtOAc was added. The organic layer was separated,washed with brine, dried (MgSO₄), filtered and the solvent wasevaporated to give 23.8 g (70%) of intermediate 132 used without furtherpurification.

Intermediate

was prepared according to the above protocol for intermediate 114.

b) Preparation of Intermediate 115

A 1M solution of tetrabutylammonium fluoride in THF (24 mL; 24 mmol) wasadded dropwise to a solution of intermediate 114 (12.5 g; 24 mmol) inTHF (250 mL) at room temperature. The reaction mixture was stirred atroom temperature for 18 hours. The mixture was poured out into icewater, basified with K₂CO₃ 10% and EtOAc was added. The organic layerwas separated, washed with brine, dried (MgSO₄), filtered and thesolvent was evaporated to dryness. The residue was crystallized fromdiethyl ether. The precipitate was filtered off and dried to afford 8.8g (90%) of intermediate 115. MP: 118° C. (Kofler).

c) Preparation of Intermediate 116

Methanesulfonyl chloride (1.9 mL; 24.7 mmol) was added dropwise to asolution of intermediate 115 (2 g; 5.0 mmol), triethylamine (4.9 mL;34.5 mmol) in DCM (80 mL) at 5° C. under a N₂ flow. The reaction mixturewas stirred at room temperature for 3 hours. The reaction mixture waspoured out into ice water and DCM was added. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated todryness to give 3.4 g of intermediate 116 used without furtherpurification for the next step.

d) Preparation of Intermediate 117

NaH (0.42 g; 10.4 mmol) was added portionwise todi-tert-butyl-iminocarboxylate (2.3 g; 10.4 mmol) inN,N-dimethylformamide (40 mL). The reaction mixture was stirred at 10°C. for 30 minutes. Then intermediate 116 (2.5 g; 5.2 mmol) was addeddropwise under N₂ flow. The reaction mixture was stirred at roomtemperature for 18 hours, then stirred at 50° C. for 4 hours. Thereaction was poured out into ice water and EtOAc was added. The organiclayer was separated and washed with brine, dried (MgSO₄), filtered andthe solvent was evaporated. The residue (4 g) was purified bychromatography over silica gel (15-40 μm; 80 g; mobile phase 98% DCM,20% MeOH). The pure fractions were collected and concentrated to give1.7 g (54%) of intermediate 117.

e) Preparation of Intermediate 118

Trifluoroacetic acid (3 mL; 39.7 mmol) was added to a solution ofintermediate 117 (1.5 g; 2.5 mmol) in DCM (20 mL). The reaction wasstirred at room temperature for 5 hours. The reaction mixture was pouredout into ice water, basified with K₂CO₃ 10%, EtOAc was added. The layerswere separated then the aqueous layer was evaporated till dryness. Theresidue was dissolved in MeOH. The precipitate was filtered off and thefiltrate was evaporated till dryness. The residue was dissolved in DCM.The precipitate was filtered off and the filtrate was evaporated tilldryness to afford 0.45 g (45%) of intermediate 118. MP: 96° C. (Kofler).

Example A48 a) Preparation of Intermediate 119

Thionyl chloride (26 mL; 359 mmol) was added dropwise to a solution of3-amino-5-methoxybenzoic acid (10 g; 59.82 mmol) in MeOH (150 mL) at 0°C. The reaction mixture was stirred for 2 hours at room temperature. Theprecipitate was filtered off, washed with DIPE and dried under vacuo at50° C. to give 8.6 g (79%) of intermediate 119 (a white solid).

b) Preparation of Intermediate 120

A solution of lithium 2.4M in THF (35.8 mL; 85.9 mmol) was addeddropwise to a solution of intermediate 119 (8.62 g; 39.6 mmol) in dryTHF (150 mL) at 0° C. under a N₂ flow. The reaction mixture was stirredfor 2 hours at room temperature. The reaction mixture was treated withNH₄Cl and stirred for 10 minutes at 0° C. The precipitate was filteredoff and washed with EtOAc. The filtrate was separated and the organiclayer was washed with brine, dried (MgSO₄), filtered and the solvent wasevaporated to dryness. The residue (6 g) was purified by chromatographyover silica gel (200 g; mobile phase gradient from 100% DCM to 7% MeOHin DCM). The pure fractions were collected and concentrated to give 3.26g of intermediate 120.

c) Preparation of Intermediate 121

Under an inert atmosphere, a solution of tris(dibenzylacetone)palladium(0) (1.12 g; 1.2 mmol),2-dicyclohexylphospino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (1.28 g; 2.7mmol) was added to room temperature to a solution of intermediate 2(3.52 g; 12.2 mmol), intermediate 120 (3.3 g; 17.45 mmol) and cesiumcarbonate (11.9 g; 36.49 mmol) in t-BuOH (80 mL). The reaction mixturewas stirred at 105° C. for 1 hour using one single mode microwave. Thereaction mixture was cooled to room temperature, poured out into icewater (400 mL) and was stirred for 15 minutes. The precipitate wasfiltered off and washed with water. The precipitate was dissolved inDCM/MeOH (95/5) and the insoluble product was filtered off and dried togive 4.7 g of intermediate 121 used without further purification for thenext step.

d) Preparation of Intermediate 122

MnO₂ (5.65 g; 65 mmol) was added to a solution of intermediate 121 (4.7g; 13 mmol) in THF (270 mL). The reaction mixture was stirred at roomtemperature for 18 hours. The reaction mixture was filtered over a padof Celite®. The filtrate was evaporated to give 1.5 g (32%) ofintermediate 122 used without further purification for the next step.

e) Preparation of Intermediate 123

Intermediate 122 (0.3 g; 0.64 mmol) and diethylamine (0.14 g; 1.9 mmol)were added to Pd/C 10% (0.05 g) and 0.2 mL of a 4% solution of thiophenein DIPE in MeOHITHF (100 mL) under N₂ flow. The reaction mixture wasstirred at 50° C. under 75 atm H₂ atmosphere until 1 eq hydrogen wasabsorbed. The reaction mixture was filtered over a pad of Celite®. Thefiltrate was evaporated to give 0.354 g of the intermediate 123.

Example A49 Preparation of Intermediate 124

A mixture of 3-bromo-5-methoxyphenol (2 g; 9.8 mmol), cesium carbonate(6.4 g; 19.7 mmol) in N,N-dimethylformamide (20 mL) and water (4 mL) wasdegassed under N₂ flow for 1 hour, then aceticacid-2-chloro-2,2-difluoro-sodium salt (5.3 g; 34.5 mmol) was added. Thereaction mixture was stirred at 120° C. for 2 days. The reaction waspoured out into ice water and EtOAc was added. The organic layer wasseparated and washed with brine, dried (MgSO₄), filtered and the solventwas evaporated. The residue (2.5 g) was purified by chromatography oversilica gel (Irregular SiOH, 15-40 μm, 300 g; mobile phase gradient from95% Heptane, 5% EtOAc to 90% Heptane, 10% EtOAc). The pure fractionswere collected and concentrated to give 0.56 g (23%) of intermediate124.

Example A50 a) Preparation of Intermediate 133

A mixture of 2-chloro-4-methoxypyrimidine (1.24 g; 8.5 mmol),4-piperidinemethanol (1.2 g; 10.25 mmol) and K₂CO₃ (2.4 g; 17.0 mmol) inCH₃CN (15 mL) was stirred at 80° C. for 18 hours. The reaction mixturewas poured out into ice water and DCM was added. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated todryness. The residue (1.8 g) was purified by chromatography over silicagel (SiOH 15-40 μm, 40 g; mobile phase 0.1% NH₄OH, 99% DCM, 1% MeOH).The pure fractions were collected and concentrated to give 1.6 g (83%)of intermediate 133.

b) Preparation of Intermediate 134

Methanesulfonyl chloride (0.94 mL; 12.1 mmol) was added dropwise to asolution of intermediate 133 (0.54 g; 2.42 mmol), triethylamine (2.4 mL;16.9 mmol) in DCM (15 mL) at 5° C. under a N₂ flow. The reaction mixturewas stirred at 10° C. for 1 hour. The reaction mixture was poured outinto ice water and DCM was added. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated to dryness. The residue(1.1 g) was purified by chromatography over silica gel (SiOH 15-40 μm,40 g; mobile phase from 99% DCM, 1% MeOH). The pure fractions werecollected and concentrated to give 0.5 g (69%) of intermediate 134.

This intermediate was used in the preparation of compound 839.

Example A51 a) Preparation of Intermediate 137

4-Methyl-1-dimethylsulfamoylimidazole (2.9 g, 15.6 mmol) was diluted inTHF (105 mL). The resulting solution was cooled down to −78° C. and Nbutyl lithium 2M in cyclohexane (11.7 mL, 18.7 mmol) was added dropwise.The reaction mixture was stirred for 30 minutes at −78° C., NN-dimethylformamide (7.6 mL, 98.0 mmol) was added and the mixture wasstirred for 1 hour at −78° C., then allowed to raise to room temperaturein 1 hour. The reaction mixture was neutralized with an aqueous solutionof NH₄Cl and then poured out into water and EtOAc. The organic layer wasdried (MgSO₄), filtered and concentrated to afford 3.7 g of intermediate137.

b) Preparation of Intermediate 138

A mixture of intermediate 137 (3.7 g; 17 mmol) was dissolved in MeOH (32mL). Then the reaction mixture was cooled down to 0° C. and sodiumborohydride (0.6 g; 17 mmol) was added. The mixture was stirred for 1hour at 0° C. The reaction mixture was then concentrated, poured outinto water and EtOAc. The organic layer was dried (MgSO₄), filtered andconcentrated to afford 2.9 g (78%) of intermediate 138. It was directlyused in the next step without any further purification.

c) Preparation of Intermediate 139

Intermediate 138 (3.2 g; 14.3 mmol) was dissolved in THF (26 mL) andN,N-dimethylformamide (13 mL). Then the solution was cooled down to 0°C. and triethylamine (4.1 mL; 28.6 mmol) followed by methanesulfonylchloride (1.3 mL; 17.2 mmol) and lithium chloride (1.8 g; 43 mmol) weresuccessively added. The mixture was stirred at room temperature over 2hours. The reaction mixture was poured out into EtOAc and water. Theorganic layer was washed once with brine, dried (MgSO₄), filtered andconcentrated. The residue (3.5 g) was purified by chromatography oversilica gel (mobile phase gradient from 100% DCM to 0.1% NH₄OH, 99% DCM,1% MeOH). The pure fractions were collected, the solvent was evaporatedto afford 2.2 g (70%) of intermediate 139 used to prepare compound 695.

Example A52 Preparation of

A mixture of 3,5-dimethoxyboronic acid (18.5 g; 101.5 mmol),1-(2,2,2-trifluoroethyl)-4-piperidinemethanamine (16.6 g; 61.7 mmol),copper (II) acetate (18.5 g; 101.5 mmol) and triethylamine (59.8 mL; 425mmol) in DCM (350 mL) was stirred at room temperature for 18 hours. Themixture was filtered and the filtrate was evaporated till dryness. Theresidue was purified by chromatography over silica gel (mobile phasegradient from 89% petroleum ether/11% ethyl acetate to 45% petroleumether/55% ethyl acetate). The pure fractions were collected and thesolvent was evaporated to give 3.8 g (19%) of compound.

Example A53 Preparation of Intermediate 142

A mixture of intermediate 15 (1.8 g; 3.6 mmol) and glycine tert butylester (2.5 g; 18 mmol) in N,N-dimethylformamide (25 mL) was stirred at80° C. for 6 hours in a sealed tube. The reaction was poured out intoice water and EtOAc was added. The organic layer was separated andwashed with brine, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (2.52 g) was purified by chromatography oversilica gel (SiOH 20-45 μm, 450 g; mobile phase 0.1% NH₄OH, 96% DCM, 4%MeOH). The pure fractions were collected and concentrated to afford 0.96g (50%) of intermediate 142_used whitout further purification for thenext step.

B. Preparation of the Compounds Example B1 Preparation of Compound 1

Tetrabutylammonium fluoride (38.5 mL, 38.5 mmol;) was added dropwise toa solution of intermediate 9 (20 g, 38.5 mmol) in THF (350 mL) at roomtemperature. The reaction mixture was stirred at room temperature for 5hours. The mixture was poured out into ice water and EtOAc was added.The mixture was basified with K₂CO₃ 10% and the organic layer wasseparated, washed with brine, dried (MgSO₄), filtered and the solventwas evaporated. The residue was triturated from diethyl ether, filteredand dried under vacuum, yielding 11.7 g (75%) of compound 1. MP=153° C.(DSC).

Compound 1 was alternatively prepared using the following procedure. 525g (1.01 mol) of intermediate 9 was dissolved in a mixture of THF (0.89L), acetic acid (2.68 L) and water (0.89 L) and the reaction mixture wasstirred at 50° C. upon complete conversion to the alcohol. The reactionmixture was evaporated till dryness. The residue was taken up in DCM(3.68 L) and water (3.68 L) and the pH of the mixture was adjusted to 7using ammonia. The layers were separated. The aqueous layer wasextracted with DCM (0.5 L) and the organic layers combined, dried(MgSO₄), filtered and evaporated till dryness. The residue wascrystallized from toluene. The precipitate was filtered off, washed withtoluene and dried to provide 204 g (49.8% yield) of compound 1.

a) Preparation of Compound 2

A mixture of intermediate 47 (1.50 g; 2.476 mmol), HCl 3N (2 mL) indioxane (25 mL) was heated at 70° C. overnight. The reaction mixture wascooled to room temperature and poured out into ice water. EtOAc wasadded and the mixture was basified with an aqueous solution of K₂CO₃(10%). The organic layer was separated, washed with brine, dried(MgSO₄), filtered and the solvent was evaporated. The compound wastriturated from diethyl ether, filtered and dried under vacuum, yielding0.790 g (81%) of compound 2. MP=169° C. (DSC).

Example B2 a) Preparation of Compound 3

Tetrabutylammonium fluoride (14.6 mL, 14.6 mmol) was added dropwise to asolution of intermediate 11 (6.5 g, 12.2 mmol) in THF (100 mL) at roomtemperature. The reaction mixture was stirred at room temperatureovernight. The mixture was poured out into ice water and EtOAc wasadded. The mixture was basified with an aqueous solution of K₂CO₃ (10%)and the organic layer was separated, washed with brine, dried (MgSO₄),filtered and the solvent was evaporated to dryness to give 7.8 g ofcrude compound, which was purified by chromatography over silica gel(Irregular SiOH, 20-45 μm, 450 g MATREX; mobile phase 0.1% NH₄OH, 97%DCM, 3% MeOH). The pure fractions were collected and evaporated to yield4.9 g (96%) of compound 3. The compound was crystallized fromEt₂O/CH₃CN, the precipitate was filtered and dried to give 4.37 g (85%)of compound 3. MP=168° C. (Kofler).

Compound 3 was alternatively also prepared using the followingprocedure.

Intermediate 11 (167.2 g; 313 mmol) was added to a mixture of aceticacid (846 mL), THF (282 mL) and water (282 mL) and the mixture wasstirred at 50° C. for 18 hours and evaporated till dryness. The crudecompound 3 was used without further purification to prepare intermediate17a.

Compound 3 was alternatively also prepared using the following procedureB2b. b) HCl/i-PrOH (11.3 mL; 56.5 mmol) was added dropwise to a solutionof intermediate 18 (8.5 g; 16.87 mmol) in CH₃OH (100 mL) at 10° C., andthe mixture was stirred for 1 hour at room temperature. Ice water wasadded to the solution which was basified with NH₄OH. The product wasextracted with DCM. The organic layer was dried (MgSO₄) and evaporatedto dryness. The residue was purified by chromatography over silica gel(Irregular SiOH, 15-40 μm, 200 g; mobile phase, 97% DCM, 3% CH₃OH, 0.1%NH₄OH). The pure fractions were collected and evaporated to dryness toafford 3.7 g (52%) of compound 3 and 1.2 g of an impure fraction Thisimpure fraction was purified by chromatography over silica gel(Irregular SiOH, 15-40 μm, 300 g MERCK; mobile phase 0.5% NH₄OH, 97%DCM, 3% CH₃OH). The pure fractions were collected and the solvent wasevaporated, yielding 700 mg (10%) of compound 3.

Example B3 Preparation of Compound 4

A mixture of intermediate 10 (8.7 g; 17.99 mmol) and isopropylamine(61.3 mL, 719.68 mmol) was heated at 90° C. for 3 hours in a sealedvessel. The reaction mixture was cooled to room temperature and themixture was evaporated till dryness. DCM and water were added and theorganic layer was separated, washed with water, dried (MgSO₄), filteredand the solvent was evaporated. The residue (8 g) was crystallized fromEt₂O/CH₃CN, filtered and dried under vacuum at 60° C., yielding 6.68 g(83%) of compound 4.MP=142° C. (DSC). Compound 4 was alternativelyprepared using the following procedure.

A mixture of intermediate 10 (322 g; 666 mmol) and 2-propanamine (196.8g; 3.3 mol) in acetonitrile (2.66 L) was heated at 100° C. in a sealedvessel for 18 hours. The reaction mixture was cooled to room temperatureand concentrated to −30% of its initial volume. Water (1.5 L),2-methyltetrahydrofurane (2.5 L) and NaHCO₃ (50 g) were added. Thelayers were separated, the organic layer was washed with a solution madeof 50 g of NaHCO₃ in water (1 L), dried (MgSO₄), filtered over silicagel and evaporated till dryness. The residue was crystallized from2-propanol. The precipitate was filtered off, dried in vacuum to provide257.2 g (86.5%) of compound 4.

Compound 4 was alternatively prepared using the following procedure.

Intermediate 3 (20.0 g; 55.3 mmol), then tetra-N-butylammonium bromide(9.06 g; 27.7 mmol) were added at 2° C. under inert atmosphere to asolution of potassium hydroxide (46.6 g; 830 mmol) in THF (387 mL) andwater (6 mL). The reaction was stirred at room temperature for 2 hoursbefore portionwise addition of N-(2-chloroethyl)-2-propanamine HCl(CAS[6306-61-2]), and then at 50° C. upon complete conversion. Water wasadded, layers were separated and the organic layer concentrated, takenup in DCM/water, neutralized with HCl to neutral pH. Organic layer waswashed with water, dried (MgSO₄), filtered and evaporated till drynessto give 26.6 g of compound 4.

Compound 4 as a HCl salt (0.1HCl) was prepared using the followingprocedure.

To a stirred mixture of 2-methyltetrahydrofuran (1.5 L) and KOH (140 g,250 mmol) was added water (30 mL). Then intermediate 3 (60 g, 166 mmol))and tetrabutylammoniumbromide (13.4 g, 41 mmol) were added and themixture was heated at 50° C. for 1 hour while stirring. ThenN-(2-chloroethyl)-2-propanamine HCl (CAS[6306-61-2]) (48 g, 299 mmol)was added in 1 portion. The mixture was stirred for 18 hours at 50° C.When the conversion was complete, water (600 mL) was added to thereaction mixture. The layers were separated and the organic layer wasconcentrated. The residue was dissolved in 2-propanol (120 mL) and HClin 2-propanol was added at 60° C. After cooling, the HCl-salt wasisolated via filtration. After drying at 50° C. in a vacuum drying oventhe HCl-salt was obtained in 83% yield (compound 4a).

To 51.69 g (107 mmol) of the HCl salt from the previous step was addedwater (258 mL) and DCM (258 mL). The pH of the reaction mixture wasadjusted using ammonium hydroxide (17.25 mL) until pH=9.5. The layerswere separated and the organic layer was concentrated. The residue wascrystallized from 2-propanol (258 mL). After drying at 50° C. undervacuum compound 4 was obtained in 91% yield (43.4 g).

Example B3A Preparation of Compound 6

Intermediate 48 (7.2 g; 12.7 mmol), 3,3-difluoropyrrolidinehydrochloride (7.3 g; 50.7 mmol), sodium carbonate (6.72 g; 63.42 mmol),potassium iodide (2.1 g; 12.7 mmol) in 1-butanol (220 mL) were heated to90° C. for 15 hours. The mixture was cooled to room temperature andpoured into H₂O/K₂CO₃ and extracted with EtOAc. The organic layer wasdried (MgSO₄), filtered and evaporated to dryness. The residue waspurified by chromatography over silica gel (Irregular SiOH, 35-40 μm,Grace Resolv; mobile phase gradient from 100% DCM to 95% DCM, 5% MeOH,0.1% NH₄OH). The desired product fraction was collected and the solventwas evaporated, yielding 3.2 g (44%) of compound 6.

Example B3B Preparation of Compound 580

A mixture of intermediate 10 (2.8 g; 5.8 mmol) and1,4-dioxa-8-azaspiro[4-5]decane (1.5 g; 18 mmol) in1-methyl-2-pyrrolidinone (10 mL) in a sealed tube was heated at 140° C.using one single mode microwave (Biotage Initiator EXP 60) for 1 hour.The reaction mixture was evaporated till dryness. The crude product (6g) was purified by chromatography over silica gel (15-40 μm 300 g;mobile phase, 0.2% NH₄OH, 95% DCM, 5% MeOH). The pure fractions werecollected and the solvent was evaporated till dryness to give 1.9 g(61%) of compound 580.

Example B3C Preparation of Compound 666 and 665

A mixture of intermediate 10 (0.3 g; 0.6 mmol),2-piperidine-2-carboxamide (0.32 g; 2.5 mmol), potassium iodide (0.1 g;0.6 mmol) and carbonate sodium (0.41 g; 4.4 mmol) in 1-butanol (12 mL)was stirred at 85° C. for 4 days. The reaction was poured into ice waterand EtOAc was added. The organic layer was washed with brine, dried(MgSO₄), filtered and evaporated till dryness. The residue (0.33 g) waspurified by preparative LC on (irregular, SiOH 15-40 μM, 30 g, mobilephase gradient from 0.1% NH₄OH, 98% DCM, 2% MeOH to 0.1% NH₄OH, 96% DCM,4% MeOH). The pure fractions were collected and the solvent wasevaporated. The first product (0.1 g) was crystallized from diethylether. The precipitate was filtered and dried to give 0.081 g (25%) ofcompound 665. MP: 206° C. (Kofler). The second product (0.1 g) wascrystallized from diethyl ether. The precipitate was filtered and driedto give 0.082 g (25%) of compound 666. MP: 163° C. (Kofler).

Example B3D Preparation of Compound 677

Intermediate 10 (1.3 g; 2.7 mmol), methoxylamine hydrochloride (2.3 g;26.9 mmol) in triethylamine (15 mL; 107.5 mmol) were heated at 90° C.for 5 hours in a sealed tube. The reaction was poured out into icewater. The organic layer was separated and washed with water, dried(MgSO₄), filtered and the solvent was evaporated. The residue (2 g) waspurified by chromatography over silica gel (SiOH, 15-40 μm, 300 g;mobile phase, 96% DCM, 4% i-PrOH). The pure fractions were collected andconcentrated. The residue (0.38 g) was crystallized from diethyl ether.The precipitate was filtered and dried to afford 0.32 g (27%) ofcompound 677 MP: 177° C. (DSC).

Example B3E Preparation of Compound 923 (Free Base) and Compound 886(HCl Salt)

and as a HCl salt

A mixture of intermediate 10 (1.0 g; 2.07 mmol) and 3-pyrroline (628 μL,8.3 mmol) in aetonitrile (4 mL) was heated at 90° C. for 90 minutes in amicrowave biotage device. The reaction mixture was cooled to roomtemperature and the mixture was evaporated until dryness. DCM and waterwere added and the organic layer was separated, washed with water, dried(MgSO₄), filtered and the solvent was evaporated. The residue waschromatograohied over silica gel (5 μm, mobile phase: gradient fromNH₄OH 0.2%, DCM 98%, MeOH 2% to NH₄OH 0.8%, DCM 92%, MeOH 8%). Theeluted fractions were evaporated and the residue was dissolved in DCM,and stirred at room temperature under air bubbling. for 24 hours. Thesolvent was evaporated to give a yellow foam which was chromatographiedover silica gel (SiOH 10 μm 60 g, mobile phase 0.1% NH₄OH, 98% DCM, 2%MeOH). The desired product fractions were evaporated to provide 100 mg(11%) of compound 923. This compound was converted into the HCl salt inMeOH. The precipitate was filtered off, washed with MeOH and dried togive 41 mg (4%) of compound 886.

Example B3F Preparation of Compound 891 and 894

-   -   as a HCl salt and preparation of compound 924 and 925

A mixture of intermediate 143 (622 mg, 1.2 mmol) in isopropylamine (8.06mL, 94.6 mmol) was heated at 120° C. in a sealed vessel during 48 hours.The reaction mixture was cooled to room temperature and DCM was added.The organic layer was washed with water, dried (MgSO₄), filtered and thesolvent was evaporated to give a yellow oil. This residue was purifiedby chromatography over silica gel (5 μm, mobile phase: gradient from100% DCM to 0.7% NH₄OH, 93% DCM, 7% MeOH). The desired product fractionswere collected and evaporated yielding 33 mg (6%) of compound 924 and 40mg (7%) of compound 925. Compound 924 was converted into HCl salt inMeOH. The precipitate was filtered off, washed with Et₂O and dried togive 25 mg (4%) of compound 10891. Compound 925 was converted into HClsalt in MeOH. The solvent was evaporated, the residue was trituratedinto Et₂O, filtered off, washed with Et₂O and dried to give 51 mg (7%)of residue. This fraction was taken up from MeOH, and stirred 10 minutesat room temperature. The solvent was evaporated to dryness. The productwas triturated, and dried, to give 24 mg (3%) of compound 894.

Example B4 a) Preparation of Compound 5

A solution of intermediate 17a (0.2 g; 0.402 mmol) in2,2,2-trifluoroethylamine (2 mL; 25 mmol) was heated at 90° C. in asealed tube for 12 hours. The reaction mixture was cooled to roomtemperature and poured out into ice water. EtOAc was added and theorganic layer was separated, washed with brine, dried (MgSO₄), filteredand the solvent was evaporated. The residue was purified bychromatography over silica gel (Spherical SiOH, 10 μm, 60 g PharmPrepMERCK; mobile phase, 98% DCM, 2% CH₃OH). The pure fractions werecollected and the solvent was evaporated. The residue (0.14 g, 69%) wascrystallized from DIPE/diethyl ether/pentane (1/1/1). The precipitatewas filtered and dried under vacuum, yielding 0.134 g (67%) of compound5, MP=126° C. (DSC).

Compound 5 was alternatively also prepared using the following procedureB4b. b) 3M HCl (60 mL) was added to a solution of intermediate 17 (9.49mmol; 5.7 g) in CH₃OH (120 mL) at room temperature. The reaction mixturewas heated at 60° C. overnight. The reaction mixture was cooled to roomtemperature, diluted with DCM and poured onto an iced solution of K₂CO₃(10%). The mixture was stirred for 30 minutes and the organic layer wasdecanted, washed with water, dried (MgSO₄), filtered and evaporated todryness. The residue was purified by HPLC. The residue (5.3 g) waspurified by chromatography over silica gel (Irregular SiOH, 15-40 μm,300 g MERCK; mobile phase 0.1% NH₄OH, 98% DCM, 2% CH₃OH). The purefractions were collected and evaporated to dryness. The oily residue(3.93 g, 83%) was crystallized from DiPE/diethyl ether/CH₃CN. Theprecipitate was filtered off and dried, yielding 3.7 g (78%) of compound5.

Compound 5 was alternatively also prepared using the followingprocedure.

A mixture of intermediate 17 (268.5 g; 447 mol) and trifluoroacetic acid(0.5 L) in DCM (2.24 L) was stirred at room temperature for 18 hours andthen at 50° C. for 1 hour. The reaction mixture was evaporated tilldryness, taken up in toluene (0.3 L) and evaporated again. The residuewas dissolved in DCM (3 L) and water (2 L) and the pH adjusted toneutral with ammonia. The layers were separated, the aqueous layer wasextracted with DCM (0.3 L) and the organic layers combined andevaporated till dryness. The residue was dissolved in EtOAc (1.5 L) andstirred for 1 hour with a mixture of silica gel (275 g). The silica gelwas filtered off, washed with EtOAc and the filtrate evaporated tilldryness to give 226 g of compound 5. It was crystallized from2-propanol, filtered and dried to provide 180.8 g (80%) of compound 5.

Example B4A Preparation of Compound 7

and Compound 8

A methylamine solution in absolute ethyl alcohol (5.15 mL, 33% w/w, 41.4mmol) was added dropwise to a suspension of intermediate 10 (2 g, 4.1mmol), K₂CO₃ (2.86 g, 20.7 mmol) in dry CH₃CN (40 mL) at roomtemperature. The mixture was heated at 80° C. overnight in a sealedvessel. The reaction mixture was cooled to room temperature and pouredout into ice water. EtOAc was added and the organic layer was separated,washed with brine, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (1.85 g) was purified by chromatography oversilica gel (Irregular SiOH, 15-40 μm, 300 g MERCK; mobile phase gradientfrom 0.1% NH₄OH, 95% DCM, 5% MeOH to 0.1% NH₄OH, 90% DCM, 10% MeOH). Thedesired fractions were collected and the solvents were evaporated,yielding 0.30 g of Fraction 1 (15%) and 1.25 g of Fraction 11 (72%).Fraction I was crystallized from diethyl ether, filtered and dried undervacuum, yielding 0.240 g (12%) of compound 7. MP=160-162° C. Fraction IIwas taken up with DCM and an aqueous solution of K₂CO₃ (10%). Themixture was stirred for 1 hour, then the organic layer was separated,dried (MgSO₄), filtered and the solvent was evaporated. The product wascrystallized from diethyl ether/CH₃CN, filtered and dried under vacuumat 60° C., yielding 1.05 g (59%) of compound 8. MP=180-182° C. (Kofler).

Example B4B Preparation of Compound 679

A mixture of intermediate3-{(3-Fluoro-5-methoxyphenyl)[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}propylmethanesulfonate prepared according to A3 0.35 g; 0.72 mmol),(S)-(+)-2-pyrrolidine methanol (0.1 mL; 1 mmol) and triethylamine (0.4mL; 2.9 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was heated at 140° C.for days in a sealed tube. The reaction was poured out into ice waterand EtOAc was added. The organic layer was separated and washed withbrine, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (0.12 g) was purified by chromatography over silica gel (SiOH 5μm; mobile phase gradient from 0.52% NH₄OH, 98% DCM, 2% MeOH to 0.8%NH₄OH, 92% DCM, 8% MeOH). The pure fractions were collected andconcentrated to give 0.031 g (9%) of compound 679

Example B4C Preparation of Compound 694

as a HCl Salt

NaH (0.24 g; 5.9 mmol) was added portionwise to 2-pyrrolidinone (0.46mL; 5.9 mmol) in N,N-dimethylformamide (30 mL) at 5° C. under N₂ flow.The reaction mixture was stirred at 5° C. for 1 hour, then intermediate

prepared according to A5 (1 g; 2 mmol) was added at 5° C. under N₂ flow.The reaction mixture was allowed to warm to room temperature and stirredfor 18 hours. The reaction was poured out into ice water. A precipitatewas filtered, washed with water. The organic layer was separated andwashed with water, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (0.8 g) was purified by chromatography oversilica gel (Irregular SiOH, 15-40 μm, 300 g; mobile phase 0.1% NH₄OH,97% DCM, 3% MeOH). The pure fractions were collected and concentrated.The residue was dissolved in isopropyl alcohol and stirred at 0° C.,then 0.5 mL of HCl i-PrOH 5N was added dropwise. Diethyl ether was addedand the solution was stirred at 0° C. for 1 hour and the precipitate wasfiltered and dried to afford 0.33 g (26%) of compound 694. MP: 197° C.(DSC).

Example B5 Preparation of Compound 9

NaH (0.556 g; 13.9 mmol) was added portionwise to a solution ofintermediate 49 (3 g; 6.95 mmol) in DMF (85 mL) at 5° C. under N₂. Thereaction mixture was stirred for 30 minutes. 1-bromo-3-chloropropane (2mL; 20.9 mmol) was added dropwise and the mixture was stirred for 15hours at room temperature, then poured into H₂O/K₂CO₃ and extracted withEtOAc. The organic layer was dried (MgSO₄), filtered and evaporated todryness. The obtained residue was purified by Chromatography over silicagel (Irregular SiOH 15-40 μm, 90 g MERCK; mobile phase gradient from100% DCM to 97% DCM, 3% MeOH, 0.1% NH₄OH). The desired product fractionswere collected and the solvent was evaporated, yielding 2.94 g (86%) ofcompound 9.

a) Preparation of Compound 10

NaH (925 mg, 23.1 mmol) was added portionwise to a solution ofintermediate 3 (4.18 g, 11.6 mmol) in DMF (52 mL) at 5° C. The mixturewas stirred at 5° C. for 30 minutes, then a solution of4-(phenylmethyl)-2-morpholinemethanol 2-methanesulfonate (4.95 g, 17.3mmol) in DMF (13.5 mL) was added. The reaction mixture was heated at 60°C. for 18 hours. The mixture was poured into water and the product wasextracted with EtOAc. The organic layer was washed with water and brine,dried (MgSO₄), filtered and evaporated. The obtained residue waspurified by chromatography over silica gel (Irregular SiOH, 15-40 μm,300 g MERCK; mobile phase 0.1% NH₄OH, 97% DCM, 3% MeOH). The desiredproduct fraction was collected and the solvent was evaporated, yielding2.74 g (43%, purity 90%) of a yellow foam. A sample (440 mg) waspurified by achiral super critical fluid chromatography (AMINO 6 μm150×21.2 mm; mobile phase, 0.3% 2-propylamine, 20% MeOH, 80% CO₂). Thedesired product fraction was collected and the solvent was evaporated,yielding 356 mg of a residue which was crystallized withDCM/Acetone/diethyl ether. The precipitate was filtered off and dried togive 188 mg of compound 10. MP=134° C. (Kofler).

b-1) Preparation of Compound 11

To a solution of intermediate 3 (67 mg, 0.18 mmol) in tetrahydrofuran (4mL) was added NaH (12 mg, 0.28 mmol). The suspension was stirred at roomtemperature until no bubbles were observed, cooled to 0° C. and methyliodide (0.08 mL, 1.3 mmol) was added drop wise. The reaction mixture wasstirred at room temperature overnight, diluted with EtOAc and washedwith brine. The organic layer was separated, dried (Na₂SO₄) andconcentrated. The crude residue was purified by chromatography oversilica gel to afford 38 mg (54%) of compound 11 (yellow powder).

b-2) Preparation of Compound 12

To a solution of intermediate 3 (100 mg, 0.277 mmol) in tetrahydrofuran(3 mL) was added potassium hexamethyldisilazide (0.5M in toluene, 12 mg,0.831 mmol). The reaction mixture was stirred at room temperature for 30minutes and propyl bromide (0.30 mL) was added drop wise. The reactionmixture was stirred at room temperature for a further 3 hours anddiluted with DCM and water. The solid residue was removed by filtration,dissolved in MeOH and combined with the other organic extracts, dried(MgSO₄) and then concentrated. The crude residue was purified bychromatography over silica gel to afford 10 mg (9%) of compound 12(yellow powder).

b-3) Preparation of Compound 13

A mixture of intermediate 3 (50 mg, 0.139 mmol), cesium carbonate (226mg, 0.693 mmol) and 1-bromo-2-methyl propane (95 mg, 0.693 mmol) inCH₃CN (1 mL) was heated. The reaction mixture was heated in a CEMDiscovery microwave at 100° C. for 1 hour. Upon cooling, the reactionmixture was partitioned between DCM and water. The organic layer wasseparated and the aqueous layer was extracted with further DCM. Thecombined organic layers were dried (MgSO₄) and concentrated. The cruderesidue was purified by chromatography over silica gel to afford 5 mg(9%) of compound 13 (yellow powder).

Example B6 Preparation of Compound 14

and Compound 14a

as a HCl Salt

NaH (513.5 mg, 12.8 mmol) was added portionwise to a solution ofintermediate 8 (2.5 g, 6.4 mmol) in DMF (25 mL) at 5° C. under N₂ flow.The reaction mixture was stirred at 5° C. for 1 hour, then glycidylmethyl ether (1.1 mL, 12.8 mmol) was added dropwise at 5° C. under N₂flow. The reaction mixture was stirred for 1 hour at 5° C., then allowedto warm up to room temperature. The reaction was stirred at 80° C. for 5hours. The reaction was poured out into ice water and EtOAc was added.The organic layer was separated, washed with brine, dried (MgSO₄),filtered and the solvent was evaporated. The residue was purified bychromatography over silica gel (Irregular SiOH, 15-40 μm, 300 g MERCK;mobile phase 0.1% NH₄OH, 97.5% DCM, 2.5% MeOH). The desired productfractions were collected and the solvent was evaporated yielding 0.66 g(21.5%) of compound 14 which was converted into its HCl salt withHCl/2-propanol (5-6N) in MeOH. The mixture was evaporated, and theresulting solid was triturated into diethyl ether, filtered and dried togive 0.488 g (15%) of compound 14a (0.95 eq HCl) (mp=110° C., kofler).

Example B7 Preparation of Compound 15

HCl 3N (13.5 mL) was added to a solution of intermediate 50 (2 g, 2.98mmol) in CH₃OH (65 mL) at 5° C. The reaction mixture was stirred at roomtemperature for 2.5 hours then heated at 60° C. overnight. The solutionwas poured into ice water and basified with an aqueous solution of K₂CO₃(10%). The product was extracted with DCM. The organic layer was washedwith water, dried (MgSO₄), filtered and evaporated till dryness. Theresidue was purified by chromatography over silica gel (Irregular SiOH,20-45 μm, 450 g MATREX; mobile phase 0.1% NH₄OH, 96% DCM, 4% MeOH). Thedesired fractions were collected and the solvent was evaporated. Theresidue was purified by achiral super critical fluid chromatography on(DIETHYLAMINOPROPYL 5 μm 150×21.2 mm; mobile phase 0.3% 2-propylamine,80% CO₂, 20% MeOH). The desired fractions were collected and the solventwas evaporated. The residue was crystallized from CH₃CN/DIPE, theprecipitate was filtered off and dried, yielding 760 mg (53%) ofcompound 15. MP=121° C. (DSC).

Example B8 Preparation of Compound 16

HCl/i-PrOH (0.33 mL, 0.0017 mol) was added dropwise to a solution ofintermediate 51 (0.25 g, 0.0004 mol) in CH₃₀₀H (6 mL) at 10° C. Then themixture was stirred for 3 hours. The solution was concentrated, taken upwith iced water, basified with NH₄OH and the product was extracted withDCM. The organic layer was dried (MgSO₄) and evaporated. The residue waspurified by chromatography over silica gel (Irregular SiOH, 15-40 μm 30g; mobile phase 1% NH₄OH, 92% DCM, 8% MeOH). The desired productfraction was collected and the solvent was evaporated, yielding 138 mg(78%) of compound 16, MP=80° C. (Kofler).

Example B9 a) Preparation of Compound 17

HCl 3N (4 mL) was added dropwise to a solution of intermediate 20 (1.5g, 3.0 mmol) in dioxane (20 mL) at room temperature. The reactionmixture was heated at 70° C. overnight. The reaction was cooled to roomtemperature and poured out into ice water. EtOAc was added and themixture was basified with an aqueous solution of K₂CO₃ (10%). Theorganic layer was separated, washed with brine, dried (MgSO₄), filteredand the solvent was evaporated. The compound was crystallized fromdiethyl ether, filtered and dried under vacuum at 60° C., yielding 1 g(83%) of compound 17. MP=158-160° C. (Kofler).

Compound 17 was alternatively also prepared using the followingprocedure B9b. b) Under N₂, intermediate 19 (3.0 g; 8.1 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.9 g; 9.7mmol), sodium carbonate 2M (6.1 mL; 12.2 mmol) in ethylene glycoldimethyl ether (30 mL) were degassed by bubbling nitrogen through for 10minutes. Pd(PPh₃)₄ (0.75 g; 0.65 mmol) was added and the mixture washeated at reflux for 15 hours. The residue was poured into ice water andextracted with EtOAc. The organic layer was dried (MgSO₄), filtered andevaporated to dryness. The residue was purified by chromatography oversilica gel (Irregular SiOH, 15-40 μm, 90 g; mobile phase gradient from100% DCM to 95% DCM, 5% MeOH, 0.1% NH₄OH)₁₋₅-40 μm, 90 g). The purefractions were collected and evaporated to dryness. The obtained residuewas crystallized in DIPE, filtered and dried, yielding 1.66 g (51%) ofcompound 17.

Compound 17 was alternatively also prepared using the followingprocedure B9c. c) A mixture of intermediate 19 (3.3 g, 8.9 mmol),1,1-dimethylethyl ester4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylicacid (3.15 g, 10.7 mmol), potassium phosphate (3.79 g, 17.8 mmol),dicyclohexyl(2′,6′-dimethoxy[1,1′-biphenyl]-2-yl)phosphine (0.37 g, 0.9mmol) in dioxane (60 mL) and H₂O (6 mL) was stirred at room temperatureunder N₂ flow. After 10 minutes, Pd₂(dba)₃ (0.408 g, 0.446 mmol) wasadded portionwise at room temperature and the mixture was heated at 80°C. overnight. The reaction mixture was cooled to room temperature andpoured out into ice water. EtOAc was added and the mixture was filteredthrough a layer of celite. The celite was washed with EtOAc, then thefiltrate was extracted with EtOAc, washed with brine, dried (MgSO₄),filtered and the solvent was evaporated. The residue was purified bychromatography over silica gel (Irregular SiOH, 15/40 μm 30 g MERCK;mobile phase, gradient 100% DCM to 97% DCM, 3% MeOH). The desiredproduct fraction was collected and the solvent was evaporated, yielding3.30 g (73%) of compound 17.

Example B10 Preparation of Compound 18

At 5° C., HCl/i-PrOH 5/6N (213 μl; 1.06 mmol) was added to a solution ofintermediate 23 (250 mg; 0.53 mmol) in CH₃OH (5 mL). The reactionmixture was stirred at 5° C. for 3 hours. H₂O and ice were added. Anaqueous solution of K₂CO₃ (10%) was added until pH became basic and theproduct was extracted with DCM. The organic layer was washed with H₂O,brine dried (MgSO₄), filtered and the solvent was evaporated. The crudeproduct was taken up in diethyl ether, filtered and dried under vacuum,yielding: 64 mg (31%) of compound 18. MP=132° C. (Kofler).

Example B11 Preparation of Compound 19

A mixture of intermediate 52 (0.99 g, 1.8 mmol) in HCl 3N (3 mL) anddioxane (17 mL) was heated at 70° C. overnight. The reaction mixture wascooled to room temperature and poured out into ice water and EtOAc wasadded. The solution was basified with an aqueous solution of K₂CO₃ (10%)and the organic layer was separated, washed with brine, dried (MgSO₄),filtered and the solvent was evaporated. The residue was purified bychromatography over silica gel (Irregular SiOH, 15-40 μm 30 g MERCK;mobile phase, gradient 100% DCM to 98% DCM, 2% MeOH). The pure fractionswere collected and evaporated to dryness, yielding 782 mg (97%) ofcompound 19. MP=130° C. (Kolfer).

Example B12 Preparation of Compound 20

N3-(ethylcarbonimidoyl)-N1,N1-dimethyl-1,3-propanediamine hydrochloride(1:1) (0.12 g, 0.76 mmol) was added portionwise to a solution ofintermediate 24 (0.23 g, 0.505 mmol), 3-pyrrolidinol (0.061 g, 0.76mmol), 1-hydroxybenzotriazole (0.1 g, 0.76 mmol), Et₃N (0.105 mL, 0.76mmol) in DCM (10 mL) at room temperature. The reaction mixture wasstirred for 15 hours. The mixture was poured into H₂O and extracted withDCM. The organic layer was dried (MgSO₄), filtered and evaporated todryness. The residue was crystallized in DIPE, filtered and dried. Theproduct fraction was purified by chromatography over silica gel(Spherical SiOH, 10 μm 60 g, PharmPrep MERCK; mobile phase 0.5% NH₄OH,94% DCM, 6% MeOH). The pure fractions were collected and evaporated todryness. The residue was crystallized with DIPE, filtered and dried,yielding 186 mg (70%) of compound 20. MP=203.4° C. (DSC).

a) Preparation of Compound 21

N3-(ethylcarbonimidoyl)-N1,N1-dimethyl-1,3-propanediamine hydrochloride(1:1) (227 mg; 1.46 mmol) was added to a mixture of intermediate 53 (550mg; 0.98 mmol), methylamine hydrochloride (329 mg; 4.88 mmol), Et₃N(0.95 mL; 6.83 mmol), 1-hydroxybenzotriazole (198 mg; 1.46 mmol) in DCM(40 mL) at room temperature. The reaction mixture was stirred for 20hours, then stirred for 2 days, poured into H₂O and extracted with DCM.The organic layer was dried (MgSO₄), filtered and evaporated to dryness.The residue was purified by chromatography over silica gel (IrregularSiOH, 15-40 μm, 30 g Merck; mobile phase, gradient from 100% DCM to 90%DCM, 10% MeOH, 0.1% NH₄OH). The desired product fraction was collectedand the solvent was evaporated, yielding 76 mg (17%) of compound 21which was crystallized in diethyl ether to give 59 mg (13%) of compound21. MP=204.5° C. (DSC).

Compound 21 can also be prepared from the corresponding—O—Si(CH₃)₂—C(CH₃)₃ intermediate according to procedures describedabove, such as for example in Example B2.

Example B13 Preparation of Compound 22

A mixture of intermediate 25 (0.4 g, 1.43 mmol),1-bromo-3-isopropoxybenzene (0.46 mL, 2.86 mmol), sodium tert-butoxide(0.032 g, 0.14 mmol) and1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine](0.413 g,4.30 mmol) in ethylene glycol dimethyl ether (3 mL) was degassed with N₂for 10 minutes. Palladium(II) acetate (47% Pd) (0.032 g, 0.14 mmol) wasadded and the mixture was heated at 135° C. under microwave irradiationfor 60 minutes. The mixture was cooled to room temperature, poured intoH₂O/K₂CO₃ and extracted with EtOAc. The organic layer was dried (MgSO₄),filtered and evaporated to dryness. The residue was purified bychromatography over silica gel (Irregular SiOH, 15-40 μm 30 g; mobilephase, 0.1% NH₄OH, 99% DCM, 1% MeOH). The pure fractions were collectedand the solvent was evaporated. The residue was purified bychromatography over silica gel (X-Bridge-C18 5 μm 30*150 mm; mobilephase, gradient from 40% of a 0.5% solution of NH₄HCO₃ in water, 60%CH₃CN to 100% CH₃CN). The pure fractions were collected and the solventwas evaporated. The residue (0.187 g) was crystallized from DIPE/pentane(80/20), then the precipitate was filtered and dried under vacuum,yielding 0.128 g (22%) of compound 22. MP=109° C. (DSC).

Example B14 Preparation of Compound 23

A solution of intermediate 54 (0.4 g, 0.666 mmol) and tetrabutylammoniumfluoride (0.73 mL, 0.73 mmol) in THF (10 mL) was stirred at 0° C. for 2hours. Water and EtOAc were added, the organic layer was separated,washed with water, then brine, dried (MgSO₄), filtered and the solventwas evaporated till dryness. The residue (0.4 g) was first purified bychromatography over silica gel (Irregular SiOH 15-40 μm 300 g MERCK;mobile phase, gradient from 98% DCM, 2% MeOH to 95% DCM, 5% MeOH). Thepure fractions were collected and the solvent was evaporated. Theresidue was then purified by achiral super critical fluid chromatographyon (AMINO 6 μm 150×21.2 mm; mobile phase, 0.3% 2-propylamine, 80% CO₂,20% EtOH). The pure fractions were collected and the solvent wasevaporated. The residue (0.165 g, 51%) was crystallized from DIPE, theprecipitate was filtered and dried under vacuum, yielding 0.150 g (46%)of compound 23. MP=134° C. (Kofler).

Example B14A Preparation of Compound 691

A 1M solution of tetrabutylammonium fluoride in THF (12.7 mL; 12.7 mmol)was added dropwise to a solution of intermediate 691 (5 g; 8.5 mmol) inTHF (50 mL) at room temperature. The reaction mixture was stirred atroom temperature for 3 hours. The mixture was poured out into ice waterand EtOAc was added. The mixture was basified with K₂CO₃ 10% and theorganic layer was separated, washed with brine, dried (MgSO₄), filteredand the solvent was evaporated to dryness. The residue (3.5 g) wascrystallized from diethyl ether. The precipitate was filtered off, driedin vacuum to provide 3.2 g (80%) of compound 691MP: 99° C. (DSC).

Example B15 Preparation of Compound 24

HCl/i-PrOH (276 μL, 1.38 mmol) was added dropwise to a solution ofintermediate 55 (183 mg, 0.35 mmol) in CH₃OH (2 mL) at 10° C. and thenthe mixture was stirred for 3 hours. Diethyl ether was added and theprecipitate was filtered and dried, yielding 126 mg (76%) of compound24. MP=80° C.

Example B16 Preparation of Compound 25

as a HCl Salt

A mixture of intermediate 16 (1.37 g, 2.5 mmol) in pyrrolidine (30 mL)was heated at 80° C. for 3 hours. The mixture was cooled to roomtemperature and was evaporated until dryness. The residue was taken upin DCM and H₂O. The organic layer was extracted with DCM, dried (MgSO₄),filtered and evaporated to dryness. The residue (3 g) was purified bychromatography over silica gel (Irregular SiOH, 15-40 μm, 90 g MERCK;mobile phase, gradient from 98% DCM, 2% MeOH to 95% DCM, 5% MeOH). Thepure fractions were collected and the solvent was evaporated, yieldingthe free base. The residue was dissolved in i-PrOH, then 1.04 mL of HCl5N/i-PrOH (4 eq.) was added dropwise at 5° C. The salt was filtered,washed with DIPE and dried under vacuum at 60° C., yielding 0.53 g (40%)of compound 25. MP=259° C. (DSC).

Example B17 Preparation of Compound 26

HCl 3N (2 mL) was added dropwise to a solution of intermediate 56 (0.3g, 0.484 mmol) in dioxane (8 mL). The solution was heated at 70° C. for3 hours. The reaction was cooled to room temperature and poured out intoice water. EtOAc was added and the mixture was basified with an aqueoussolution of K₂CO₃ (10%). The organic layer was separated, washed withbrine, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (0.19 g) was crystallized from DIPE/CH₃CN. The precipitate wasfiltered and dried under vacuum, yielding 0.112 g (56%) of compound 26.MP=202° C. (DSC).

Example B18 Preparation of Compound 27

Intermediate 57 (0.425 g; 0.88 mmol), HCl 3N (3 mL) and dioxane (8 mL)were heated to 60° C. overnight. The mixture was cooled to roomtemperature, poured into H₂O and basified with K₂CO₃. The product wasextracted with EtOAc, dried (MgSO₄), filtered and evaporated to dryness,yielding 322 mg (95%) of compound 27. MP=178° C. (DSC).

Example B19 Preparation of Compound 28

A mixture of intermediate 58 (0.3 g, 0.486 mmol) and amberlyst 15 ionexchange resin (0.03 g) in MeOH (8 mL) was stirred at 45° C. for 3hours. The resin was filtered. The filtrate was poured out into waterand was basified with an aqueous solution of K₂CO₃ (10%). EtOAc wasadded. The organic layer was separated, washed with brine, dried(MgSO₄), filtered and the solvent was evaporated. The residue (0.2 g)was purified by chromatography over silica gel (Irregular SiOH, 15-40μm, 30 g MERCK; mobile phase, gradient from 98% DCM, 2% MeOH to 95% DCM,5% MeOH). The pure fractions were collected and the solvent wasevaporated. The residue (0.18 g) was crystallized from DIPE/CH₃CN(80/20). The precipitate was filtered off and dried under vacuum,yielding 0.114 g (52%) of compound 28. MP=142° C. (DSC).

Example B20 Preparation of Compound 29

A 2M solution of methylamine in THF (4.8 mL, 0.0097 mol) was added to asolution of intermediate 26 (0.14 g, 0.0003 mol) and K₂CO₃ (0.1 g,0.0007 mol) in THF (5 mL). The solution was heated to 100° C. in asealed tube for 24 hours, then cooled to room temperature and pouredinto H₂O/NaCl. The mixture was extracted with DCM. The organic layer wasdried (MgSO₄), filtered and evaporated to dryness. The residue waspurified by chromatography (Irregular SiOH, 15-40 μm, 30 g; mobilephase, 95% DCM, −5% MeOH, 0.1% NH₄OH). The product fractions werecollected and the solvent was evaporated, yielding 103 mg (86%) ofcompound 29. MP=80° C. (Kofler).

Example B21 Preparation of Compound 301

HCl/i-PrOH (0.4 mL, 0.002 mol) was added dropwise to a solution ofintermediate 59 (0.31 g, 0.0005 mol) in CH₃OH (5 mL) at 10° C. and themixture was stirred for 2 hours. The solution was evaporated to dryness,then the residue was taken up with ice water, basified with NH₄OH andthe product was extracted with DCM. The organic layer was dried (MgSO₄)and evaporated to dryness. The residue was purified by chromatographyover silica gel (Sunfire Silica 5 μm 150×30.0 mm); mobile phase,gradient from 0.2% NH₄OH, 98% DCM, 2% MeOH to 1.1% NH₄OH, 89% DCM, 11%MeOH). The product fractions were collected and the solvent wasevaporated, yielding 106 mg (47%) of compound 30. MP=80° C. (Kofler).

Example B22 Preparation of Compound 31

To intermediate 28 (0.4 g, 0.92 mmol) in dioxane (8 mL) was addedcyanogenbromide (0.099 g, 0.93 mmol) at room temperature. Then sodiumhydrogenocarbonate (0.0775 g, 0.92 mmol) in H₂O (distilled, 4.8 mL) wasadded. The mixture was stirred at room temperature for 5 hours. Themixture was extracted with EtOAc and dried (MgSO₄), filtered andevaporated till dryness. The residue was taken up by diethyl ether,filtered and dried to give 0.42 g (99%) of compound 31. MP=254° C.(Kofler).

Example B23 Preparation of Compound 32

Hydrazine monohydrate (81 μL, 2.58 mmol) was added to a solution ofintermediate 27 (0.21 g, 0.37 mmol) in EtOH (10 mL). The mixture washeated at 80° C. for 5 hours. The mixture was cooled to roomtemperature, evaporated and the residue was poured into water. Theaqueous layer was extracted with DCM, washed with brine, dried (MgSO₄),filtered and evaporated to dryness. The residue was purified bychromatography (Irregular SiOH, 15-40 μm, 10 g; mobile phase, 95% DCM-5%MeOH-0.5% NH₄OH). The pure fractions were collected and the solvent wasevaporated, yielding 97 mg (59%) of compound 32, MP=80° C. (Kofler).

Example B24 Preparation of Compound 33

Intermediate 31 (270 mg, 0.59 mmol), sodium triacetatohydroborate (312mg, 1.475 mmol) and isopropylamine (100 μl, 1.2 mmol) in CH₃CN (6 mL)were stirred at room temperature for 24 hours. Isopropylamine (500 μl,5.8 mmol) was added and the reaction mixture was stirred at roomtemperature for 12 hours, then sodium triacetatohydroborate (312 mg, 1.5mmol) was added and the reaction mixture was stirred for 24 hours. 10%K₂CO₃ aqueous solution was added. The reaction mixture was extractedtwice with DCM, dried (MgSO₄), filtered and evaporated. The residue (437mg) was purified by chromatography over silica gel (Sunfire Silica 5 μm150×30.0 mm mobile phase, gradient from 0.2% NH₄OH, 98% DCM, 2% MeOH to0.8% NH₄OH, 92% DCM, 8% MeOH). The desired product fraction wascollected and the solvent was evaporated, to give 113 mg of compound 33(cis).

Example B25 Preparation of Compound 34

Intermediate 29 (0.5 g, 0.8 mmol) and methylamine 40% in H₂O (28 mL,0.33 mol) were heated in dioxane (20 mL) at 120° C. in a sealed tube for5 hours. The solution was cooled and evaporated to dryness. The residuewas purified by chromatography over silica gel (Sunfire Silica 5 μm150×30.0 mm; mobile phase, gradient from 0.2% NH₄OH, 98% DCM, 2% MeOH to1.4% NH₄OH, 86% DCM, 14% MeOH). The pure fractions were collected andthe solvent was evaporated. The product was crystallized with diethylether. The precipitate was filtered and dried, yielding 118 mg (31%) ofcompound 34, MP=174° C. (DSC).

Example B26 Preparation of Compound 35

To a mixture of intermediate 60 (268 mg, 0.51 mmol) was added THF (20mL), followed by tetrabutylammonium fluoride (2.53 mL, solution 1M inTHF; 2.53 mmol). The reaction mixture was stirred at room temperatureovernight. The reaction mixture was concentrated. EtOAc and H₂O wereadded and the two phases were separated. The organic phase was dried(MgSO₄), filtered and concentrated. The residue was purified bychromatography over silica gel (Hyperprep C18 HS BDS100A 8 mu (Shandon);mobile phase, gradient from 90% of a 0.25% solution ofammoniumbicarbonate in water, 10% CH₃CN to 100% CH₃CN). The productfractions were collected and the solvent was evaporated. The residue wasdissolved in CH₃CN/H₂O and lyophilized, yielding 55 mg of compound 35.

Example B27 Preparation of Compound 36

A mixture of 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline (521 mg,1.8 mmol), intermediate 38 (377 mg, 1.8 mmol), sodium tert-butoxide (520mg, 5.4 mol) in dioxane (10 mL) was degassed at room temperature underN₂ flow. After 10 minutes, palladium(II) acetate (47% Pd) (20 mg, 0.09mmol) and1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine](56 mg,0.09 mmol) were added portionwise at room temperature under N₂ flow. Thereaction mixture was heated at 90° C. overnight, then cooled to roomtemperature and partitioned between water and DCM. The organic layer wasdried (MgSO₄), filtered and concentrated. The residue was purified bychromatography over silica gel (Irregular SiOH, 15-40 μm, 30 g mobilephase, 98% DCM, 2% MeOH). The product fractions were collected and thesolvent was evaporated. The residue was again purified by achiral supercritical fluid chromatography on (2 ETHYLPYRIDINE 6 μm 150×21.2 mm;mobile phase, 0.3% 2-propylamine, 15% MeOH, 85% CO₀₂). The productfractions were collected and the solvent was evaporated. The residue wastaken up in diethyl ether, filtered and dried, yielding 0.209 g (27%) ofcompound 36. MP=164° C. (kofler).

Example B27A Preparation of Compound 920

A mixture of intermediate

(see A52) (0.5 g; 1.5 mmol), intermediate 2 (0.36 g; 1.3 mmol) andsodium tert-butoxide (0.36 g; 1.3 mmol) in dry dioxane (40 mL) wasdegassed at room temperature under N₂ flow. After 10 minutes,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (50 mg; 0.13mmol) and tris(dibenzylideneacetone)dipalladium(0) (115 mg; 0.13 mmol)were added and the reaction mixture was heated at 100° C. for 4 hours.The reaction mixture was cooled to room temperature, poured into amixture of water and brine, filtered through a pad of Celite®, extractedwith EtOAc, washed with water, dried (MgSO₄), filtered and evaporated todryness to give 1.1 g of residue. The residue was purified bychromatography over silica gel (5 μm, mobile phase: gradient from 71%Heptane, 1% MeOH, 28% AcOEt to 20% MeOH, 80% AcOEt). The desiredfractions were collected and evaporated to give 240 mg of residue. Theresidue was taken-up in Et₂O, filtered and dried to give 144 mg ofcompound 920, mp=123° C. (DSC).

Example B28 Preparation of Compound 37

At 0° C., potassium permanganate (0.117 g, 0.738 mmol) was added to asolution of compound 51 (0.326 g, 0.738 mmol) in acetone (10 mL) and H₂O(2.5 mL). The solution was stirred at room temperature overnight and wasthen poured on ice water. DCM was added and the mixture was filteredthrough a celite layer. The organic layer was extracted, dried (MgSO₄)and evaporated to dryness. The residue (0.23 g) was purified bychromatography over silica gel (Spherical SiOH, 10 μm, 60 g PharmPrepMERCK; mobile phase, 95% DCM, 5% MeOH, 0.1% NH₄OH). The desired productfraction was collected and the solvent was evaporated, yielding 0.150 gof compound 37, which was crystallized in DIPE, filtered and dried,yielding 0.139 g (40%) of compound 37. MP=154° C. (DSC).

Example B29 Preparation of Compound 38

A mixture of intermediate 62 (3.9 g, 8.3 mmol) and K₂CO₃ (1.15 g, 8.3mmol) in MeOH (150 mL) was stirred at room temperature for 18 hours. Thereaction mixture was quenched with water and extracted with DCM. Theorganic layer was decanted, washed with brine, dried (MgSO₄), filteredand evaporated to dryness. The solid residue was taken up with diethylether and the precipitate was filtered off and dried, yielding 2.84 g(85%) of compound 38. MP=168° C., (Kofler).

Example B30 Preparation of Compound 39

and Compound 40 as a HCl Salt

Intermediate 10 (365 mg, 0.75 mmol) in 3,5-dimethylpiperidine (5 mL) washeated to 80° C. overnight. Then 5 mL of 3,5-dimethylpiperidine wasadded to the solution and heated at 80° C. for 5 hours. The solution wasevaporated to dryness, then the residue was poured into H₂O andextracted with EtOAc. The organic layer was dried (MgSO₄), filtered andevaporated. The residue (853 mg) was purified by chromatography oversilica gel (Sunfire Silica 5 μm 150×30.0 mm; mobile phase, gradient from0.1% NH₄OH, 99% DCM, 1% MeOH to 0.8% NH₄OH, 92% DCM, 8% MeOH). Thedesired product fractions were collected and the solvents wereevaporated to give 41.8 mg (11%) of Fraction 1 and 115.7 mg (31%) ofcompound 39. MP=80° C. (Kofler) (gummed). Fraction I was dissolved inisopropyl alcohol. The mixture was stirred at 0° C., then 67 μL (4 eq)of HCl in isopropyl alcohol 5N was added dropwise to the mixture.Diethyl ether was added to the solution and was stirred at 0° C. for 1hour. The precipitate was filtered and dried to give 38.3 mg (10%) ofcompound 40 MP=80° C. (Kofler) (gummed).

Example B31 Preparation of Compound 41

A mixture of intermediate 37 (0.22 g, 0.39 mmol), hydrazine monohydrate(0.085 mL, 2.72 mmol) in EtOH (5 mL) was heated at 80° C. overnight. Thereaction mixture was cooled to room temperature and poured out into icewater. EtOAc was added and the organic layer was separated, washed withbrine, dried (MgSO₄), filtered and the solvent was evaporated tilldryness. The residue (0.250 g) was purified by chromatography oversilica gel (Spherical SiOH, 10 μm, 60 g PharmPrep MERCK; mobile phase0.1% NH₄OH, 96% DCM, 4% MeOH). The product fractions were collected andthe solvent was evaporated. The residue (0.120 g, 70%) was crystallizedfrom diethyl ether/CH₃CN, filtered and dried under vacuum at 60° C.,yielding 0.110 g (65%) of compound 41. MP 168° C. (Kofler); 169° C.(DSC).

Example B32 Preparation of Compound 33

and Compound 43

Intermediate 31 (270 mg, 0.59 mmol), sodium triacetoxyborohydride (312mg, 1.48 mmol) and isopropylamine (100 μl, 1.2 mmol) in CH₃CN (6 mL)were stirred at room temperature for 24 hours. Isopropylamine (500 μl,5.8 mmol) was added and the reaction mixture was stirred at roomtemperature for 12 hours, then sodium triacetoxyborohydride (312 mg, 1.5mmol) was added and the mixture was stirred for 24 hours. 10% K₂CO₃aqueous solution was added. The reaction mixture was extracted twicewith DCM, dried (MgSO₄), filtered and evaporated. The residue (437 mg)was purified by chromatography over silica gel (Sunfire Silica 5 μm150×30.0 mm; mobile phase, gradient from 0.2% NH₄OH, 98% DCM, 2% MeOH to0.8% NH₄OH, 92% DCM, 8% MeOH). The product fractions were collected andthe solvent was evaporated to give 113 mg (38%) of compound 33 and 42 mg(14%) of compound 43

Example B33 Preparation of Compound 604

N,N-diisopropylethylamine (0.86 mL; 5.2 mmol) and triethylamine (0.73mL; 5.2 mmol) were added to a solution of intermediate 73 (0.6 g; 0.87mmol) in methanol (7.5 mL). The reaction was stirred at 80° C. for 15hours, cooled down to room temperature and diluted with DCM and water.The organic layer was separated, washed with water, dried (MgSO₄),filtered and evaporated till dryness. The residue was purified bychromatography over silica gel (Spherical SiOH, 10 μm, 60 g; mobilephase 0.1% NH₄OH, 97% DCM, 3% MeOH). The pure fractions were collected,the solvent was evaporated. The residue (0.25 g, 59%) was crystallizedfrom diethyl ether/CH₃CN. The precipitate was filtered off and driedunder vacuum, yielding 215 mg (51%) of compound 604. MP: 157° C. (DSC)

Example B34 Preparation of Compound 605

NaH (1.1 g; 27.7 mmol) was added portionwise to N,N-dimethylformamide(100 mL), after few minutes intermediate 3 (5 g; 13.8 mmol) was addedportionwise at 5° C. under N₂ flow. The reaction mixture was stirred at5° C. for 30 minutes. Then, a solution of ethyl-2-bromopropionate (3.6mL; 27.7 mmol) in N,N-dimethylformamide (7 mL) was added dropwise at 5°C. under N₂ flow. The reaction mixture was allowed to warm to roomtemperature and stirred for 3 hours. The reaction was poured out intoice water. The precipitate was filtered, washed with water. The organiclayer was separated and washed with water, dried (MgSO₄), filtered andthe solvent was evaporated. The residue (7.51 g) was purified bychromatography over silica gel (Irregular SiOH, 20-40 μm, 450 g; mobilephase 0.1% NH₄OH, 98% DCM, 2% MeOH). The pure fractions were collectedand concentrated yielding 5.3 g (84%) of compound 605.

Example B35 Preparation of a Compound 607 (Mixture of Enantiomers)

A solution of intermediate 74 (8 g; 16.08 mmol) and potassium phtalimide(6 g; 32.16 mmol) in CH₃CN (110 mL) was heated at 120° C. for 2 hoursusing one single mode microwave. The reaction mixture was cooled to roomtemperature and poured out into ice water. The precipitate was filtered,washed with water and DCM. The organic layer was separated and washedwith water, dried (MgSO₄), filtered and the solvent was evaporated togive 7.4 g of compound 607 used without further purification for thenext step.

Example B36 Preparation of Compound 313

A 1M solution of tetrabutylammonium fluoride in THF (7.7 mL; 7.7 mmol)was added dropwise to a solution of intermediate 76 (3.5 g; 5.9 mmol) inTHF (75 mL) at room temperature. The reaction mixture was stirred atroom temperature for 3 hours. The mixture was poured out into ice waterand EtOAc was added. The mixture was basified with K₂CO₃ 10% and theorganic layer was separated, washed with brine, dried (MgSO₄), filteredand the solvent was evaporated to dryness. The residue (4.4 g) wascrystallized from diethyl ether. The precipitate was filtered off, driedin vacuum to provide 2.62 g (93%) of compound 313 MP: 176° C. (DSC).

Example B37 Preparation of Compound 615

A mixture of intermediate 77 (2 g; 3.6 mmol) and isopropylamine (1.55 g;18 mmol) in acetonitrile (30 mL) was heated at 100° C. in a sealedvessel for 18 hours. The reaction mixture was cooled to roomtemperature. The reaction mixture was poured out into ice water, EtOAcwas added. The organic layer was separated, washed with a solution ofNaHCO₃, dried (MgSO₄), filtered and evaporated till dryness. The residue(2.5 g) was purified by chromatography over silica gel (Irregular SiOH,20-40 μm, 450 g; mobile phase 0.5% NH₄OH, 90% DCM, 10% MeOH). The purefractions were collected and concentrated. The residue (0.85 g) wascrystallized from diethyl ether, the precipitate was filtered off, driedin vacuum to provide 0.76 g (41%) of compound 615.MP: 134° C. (DSC)

Example B38 Preparation of Compound 616

Trifluoroacetic acid (6.5 mL; 84.8 mmol) was added to a solution ofintermediate 82 in DCM (50 mL) at 10° C. The reaction mixture wasstirred at room temperature for 18 hours. The reaction mixture wasconcentrated, the residue was taken-up with DCM, washed with K₂CO₃ 10%.The organic layer was dried (MgSO₄), filtered and evaporated to dryness.The residue was crystallized from diethyl ether. The precipitate wasfiltered off, dried in vacuum to provide 0.65 g (65%) of compound616.MP: 170° C. (Kofler)

Example B39 Preparation of Compound 617

A 1M solution of tetrabutylammonium fluoride in THF (1.82 mL, 1.8 mmol)was added dropwise to a solution of intermediate 85 (0.88 g, 1.65 mmol)in THF (20 mL) at room temperature. The reaction mixture was stirred atroom temperature for 18 hours. The mixture was poured out into ice waterand EtOAc was added. The mixture was basified with K₂CO₃ 10%, theorganic layer was separated, washed with brine, dried (MgSO₄), filteredand the solvent was evaporated to dryness.

The residue (0.68 g) was purified by chromatography over silica gel(Spherical SiOH, 10 μm, 60 g; mobile phase 0.1% NH₄OH, 97% DCM, 3%MeOH). The pure fractions were collected and concentrated. The residue(0.54 g) was crystallized from diethyl ether. The precipitate wasfiltered off, dried in vacuum to provide 0.444 g (65%) of compound 617.MP: 149° C. (DSC)

Example B40 Preparation of Compound 618

A mixture of intermediate 86 (0.446 g; 0.91 mmol) and isopropylamine(6.2 mL; 72.3 mmol) in acetonitrile (14 mL) was heated at 140° C. in asealed vessel for 1 hour using one single mode microwave. The reactionmixture was cooled to room temperature. The reaction mixture was pouredout into ice water, EtOAc was added. The organic layer was separated,washed with a solution of NaHCO₃, dried (MgSO₄), filtered and evaporatedtill dryness. The residue (0.423 g) was purified by chromatography oversilica gel (Spherical SiOH, 10 μm, 60 g; mobile phase 0.5% NH₄OH, 95%DCM, 5% MeOH). The pure fractions were collected and concentrated. Theresidue (0.3 g) was crystallized from diethyl ether, the precipitate wasfiltered off, dried in vacuum to provide 0.21 g (52%) of compound618.MP: 139° C. (DSC).

Example B41 Preparation of Compound 619

as a HCl Salt

A mixture of intermediate 87 (1.26 g; 0.99 mmol), hydrazine monohydrate(0.22 mL; 7.0 mmol) in EtOH (20 mL) was stirred at 80° C. for 3 hours.The reaction mixture was cooled to room temperature and poured out intoice water. The organic layer was separated, washed with brine, dried(MgSO₄), filtered and the solvent was evaporated until dryness. Theresidue (0.566 g) was purified by chromatography over silica gel (SiOH,5 μm, 150*30 mm; mobile phase gradient 0.2% NH₄OH, 98% DCM, 2% MeOH to1.2% NH₄OH, 88% DCM, 12% MeOH). The product fractions were collected andthe solvent was evaporated. The residue (0.385 g, 77%) was dissolved inisopropyl alcohol. The reaction mixture was stirred at 0° C. then 0.6 mLof HCl in isopropyl alcohol 5N was added dropwise to the solution.Diethyl ether was added to the solution and was stirred at 0° C. for 1hour.

The precipitate was filtered off, dried in vacuum to provide 0.42 g(69%) of compound 619.MP: 210° C. (Kofler)

Example B42 a) Preparation of Compound 620

A mixture of intermediate 10 (1.4 g; 2.9 mmol), tert butyl(1S,4S)-(−)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.69 g; 3.5mmol) and K₂CO₃ (0.8 g; 5.8 mmol) in CH₃CN (20 mL) was stirred at 80° C.for 48 hours.

The reaction mixture was cooled to room temperature, poured out into icewater EtOAc was added. The organic layer was separated, washed withbrine, dried (MgSO₄), filtered and the solvent was evaporated untildryness. The residue (1.6 g) was purified by chromatography over silicagel (Irregular SiOH, 20-45 μm, 450 g; mobile phase 0.1% NH₄OH, 94% DCM,6% MeOH). The product fractions were collected and the solvent wasevaporated. The residue (0.74 g) was purified with super critical fluidchromatography (Amino 6 μm, 150*21.1 mm; mobile phase 90% CO₂, 10%MeOH). The product fractions were collected and the solvent wasevaporated. The residue (0.6 g, 36%) was crystallized from diethylether. The precipitate was filtered off, dried in vacuum to provide0.444 g (26%) of compound 620. MP: 114° C. (Kofler)

b) Preparation of Compound 621

as a HCl Salt

A 5N solution of HCl in i-PrOH (0.48 mL, 2.4 mmol) was added dropwise toa solution of compound 620 (0.35 g, 0.6 mmol) in CH₃OH (10 mL) at 5° C.and the mixture was then stirred 3 days at room temperature. Diethylether was added and the precipitate was filtered off, was dried undervacuum to afford 0.33 g (94%) of the compound 621.MP: >260° C. (Kofler)

Example B43 Preparation of Compound 622

A 1M solution of tetrabutylammonium fluoride in THF (1.1 mL; 1.1 mmol)was added dropwise to a solution of intermediate 88(0.43 g; 0.79 mmol)in THF (6 mL) at room temperature. The reaction mixture was stirred atroom temperature for 18 hours. The mixture was poured out into icewater. The precipitate was filtered off, washed with water and CH₃CN anddried to afford 0.13 g (40%) of compound 622. MP: 190° C. (Kofler)

Example B44 Preparation of Compound 623

as a HCl Salt

A mixture of intermediate 89 (0.26 g; 0.43 mmol) and isopropylamine (5mL) in acetonitrile (2 mL) was heated at 90° C. in a sealed vessel for18 hours. The reaction mixture was cooled to room temperature. Thereaction mixture was poured out into ice water, DCM was added. Theorganic layer was separated, washed, dried (MgSO₄), filtered andevaporated till dryness. The residue (0.28 g) was purified bychromatography over silica gel (Irregular SiOH, 15-40 μm, 30 g; mobilephase 0.4% NH₄OH, 96% DCM, 4% MeOH). The pure fractions were collectedand concentrated. The residue (0.156 g, 77%) was dissolved in CH₃CN. HClin isopropyl alcohol 5N was added dropwise to the solution. The solventwas evaporated, dried in vacuum to give 0.162 g (70%) of compound 623.MP: 133° C. (Kofler)

Example B45 Preparation of Compound 630

NaH (0.54 g; 13.3 mmol) was added portionwise to intermediate 3 (2.4 g;6.66 mmol) in NN-dimethylformamide (36 mL). The reaction mixture wasstirred at 0° C. for 30 minutes. Then intermediate 91 (2.2 mL; 10 mmol)was added dropwise at 5° C. under N₂ flow. The reaction mixture wasstirred at room temperature for 18 hours. The reaction was poured outinto ice water and EtOAc was added. The organic layer was separated andwashed with brine, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (4.2 g) was purified by chromatography oversilica gel (Irregular SiOH 15-40 μm, 300 g; mobile phase 0.1% NH₄OH,98.5% DCM, 1.5% MeOH). The pure fractions were collected andconcentrated to give 0.793 g (21%) of compound 630. MP: 67° C. (Kofler).

Example B46 Preparation of Compound 632

Trifluoroacetic acid (0.073 mL; 0.25 mmol) was added to a solution ofintermediate 92 (0.135 g; 0.25 mmol) in THF (5 mL). The reaction wasstirred at room temperature for 24 hours. The reaction mixture waspoured out into ice water; EtOAc was added. The organic layer wasseparated, washed with brine, dried (MgSO₄), filtered and the solventwas evaporated. The residue (0.151 g) was purified by chromatographyover silica gel (SiOHSiOH, 5 μm, 150*30 mm; mobile phase gradient from70% Heptane, 2% MeOH, 28% EtOAc to 20% MeOH, 80% EtOAc). The purefractions were collected and concentrated. The residue (0.04 g) wascrystallized from diethyl ether. The precipitate was filtered and driedto afford 0.033 g (31%) of compound 632. MP: 156° C. (DSC)

Example B47 Preparation of Compound 638

NaH (0.65 g; 16.6 mmol) was added portionwise to intermediate 3 (3 g;8.3 mmol) in N,N-dimethylformamide (25 mL). The reaction mixture wasstirred at 10° C. for 30 minutes. Then 3-chloro-3-methyl-1-butyne (1.2g; 10.8 mmol) was added dropwise under N₂ flow. The reaction mixture wasstirred at room temperature for 48 hours. The reaction was poured outinto ice water and EtOAc was added. The organic layer was separated andwashed with brine, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (4 g) was purified by chromatography over silicagel (mobile phase gradient from 71% Heptane, 1% MeOH, 28% EtOAc to 20%MeOH, 80% EtOAc). The pure fractions were collected and concentrated togive 0.152 g (4%) of compound 638 used without further purification forthe next step.

Example B47A Preparation of Compound 919

Sodium hydride (0.24 g; 6.1 mmol) was added portionwise to a solution ofintermediate 3 (1.1 g; 3 mmol) in DMF (10 mL) at 5° C. under N₂ flow.The reaction mixture was stirred at 5° C. for 30 minutes. Then asolution of (4-chloro-2-butyn-1-yl)-benzene (1 g; 6.1 mmo)) was addeddropwise at 5° C. under N₂ flow. The reaction mixture was stirred for 1hour at 5° C., then stirred at room temperature overnight. The reactionwas poured out into ice water and EtOAc was added. The organic layer wasseparated, washed with brine, dried (MgSO₄), filtered and the solventwas evaporated to dryness. The residue was purified by chromatographyover silica gel (SiOH 15-40 μm 300 g, mobile phase: 0.1% NH₄OH, 98% DCM,2% MeOH). The desired fractions were collected and evaporated to give0.66 g of residue which was then purified by achiral Supercritical FluidChromatography on (5 μm, mobile phase, 60% CO₂, 40% mixture ofMeOH/iPrOH 50/50 v/v). The desired fractions were collected andevaporated to give 282 mg (19%) of compound 919. This fraction wascrystallized from Et₂O to give 143 mg of compound 919 (mp=130° C.).

Example B48 Preparation of Compound 641

A mixture of intermediate 17a (0.3 g; 0.6 mmol), glycinamidehydrochloride (0.2 g; 1.8 mmol), potassium iodide (0.1 g; 0.6 mmol),sodium carbonate (0.32 g; 3.0 mmol) in 1-BuOH (12 mL) was stirred at 85°C. for 18 hours. The reaction was poured out into ice water and EtOAcwas added. The organic layer was separated and washed with brine, dried(MgSO₄), filtered and the solvent was evaporated. The residue (0.28 g)was purified by chromatography over silica gel (SiOH 5 μm, 150*30 mm;mobile phase gradient from 0.2% NH₄OH, 98% DCM, 2% MeOH to 0.9% NH₄OH,91% DCM, 9% MeOH). The pure fractions were collected and concentrated.The residue (0.100 g) was crystallized from diethyl ether. Theprecipitate was filtered and dried to afford 0.081 g (28%) of compound641. MP: 155° C. (DSC).

Example B49 Preparation of Compound 137

A mixture of intermediate 93 (12.8 g; 23.4 mmol) and isopropylamine (61mL; 500 mmol) in acetonitrile (500 mL) was heated at 100° C. in a sealedvessel for 18 hours. The reaction mixture was cooled down to roomtemperature. The reaction was poured out into ice water and EtOAc wasadded. The organic layer was washed with brine, dried (MgSO₄), filteredover silica gel and evaporated till dryness. The residue (13 g) waspurified by chromatography over silica gel (Irregular SiOH 20-40 μm,1000 g; mobile phase 0.5% NH₄OH, 95% DCM, 10% MeOH). The pure fractionswere collected and concentrated to give 8 g (55%) of the free base whichwas converted into its HCl salt as compound 137.

Example B50 Preparation of Compound 2

A 1M solution of tetrabutylammonium fluoride in THF (30.3 mL; 30.3 mmol)was added dropwise to a solution of intermediate 94 (10.2 g; 20.2 mmol)in THF (70 mL) at room temperature. The reaction mixture was stirred atroom temperature for 3 hours. The mixture was poured out into ice water,basified with K₂CO₃ 10% and EtOAc was added. The organic layer wasseparated, washed with brine, dried (MgSO₄), filtered and the solventwas evaporated to dryness. The residue was crystallized from diethylether. The precipitate was filtered off and dried to afford 5.9 g (75%)of compound 2. MP: 169° C. (DSC).

Example B51 Preparation of Compound 644

as a HCl Salt

A mixture of intermediate 100 (0.09 g; 0.14 mmol) and K₂CO₃ (0.058 g;0.42 mmol) in MeOH (1.1 mL) was stirred at room temperature for 1 hour.The reaction mixture was poured out into ice water and DCM was added.The organic layer was separated, dried (MgSO₄), filtered and the solventwas evaporated to dryness. The residue (0.2 g) was purified bychromatography over silica gel (Irregular SiOH 15-40 μm, 30 g; mobilephase 0.5% NH₄OH, 93% DCM, 7% MeOH). The pure fractions were collectedand concentrated. The residue was dissolved in EtOH/CH₃CN and acidifiedwith HCl/i-PrOH 5N. The precipitate was filtered off and dried to give0.053 g (46%) of compound 644 as a chlorhydrate.

Example B52

Alternative Preparation of Compound 93

Intermediate 3 (10 g; 27.7 mmol) was added to a solution of potassiumhydroxide (27.4 g; 415 mmol), tetrabutylammonium bromide (1.34 g; 4.0mmol) in (280 mL) and water (3 mL). The reaction mixture was stirred at50° C. for 30 minutes, then 3-bromopropylamine hydrochloride (9.7 g;44.3 mmol) was added portionwise and stirred at 50° C. for 2 hours. Thereaction mixture was cooled to room temperature. The reaction was pouredout into ice water and EtOAc was added. The organic layer was separatedand washed with brine, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (20 g) was purified by chromatography (IrregularSiOH 20-45 μm, 1000 g; mobile phase 1% NH₄OH, 90% DCM, 10% MeOH). Thepure fractions were collected and concentrated. The residue wascrystallized from diethyl ether. The precipitate was filtered and driedto give 10.5 g (90%) of compound 93. MP: 178° C. (DSC)

Example B53 Preparation of Compound 645

A 5N solution of HCl in i-PrOH (2.5 mL; 12.5 mmol) was added dropwise toa solution of intermediate 105 (0.8 g, 1.54 mmol) in CH₃OH (25 mL) at10° C. and then the mixture was stirred for 18 hours at roomtemperature. The red precipitate was filtered, rinsed with diethyl etherand dried. The precipitate was taken up with DCM and washed with asolution of NaOH 1M. The organic layer was washed with water, dried(MgSO₄), filtered and evaporated till dryness. The residue wascrystallized from diethyl ether. The precipitate was filtered and driedunder vacuum to give 0.22 g (34%) of compound 645. MP: 188° C. (DSC)

Example B54 Preparation of Compound 646

A 5N solution of HCl in i-PrOH (1.1 mL; 5.7 mmol) was added dropwise toa solution of intermediate

(0.8 g; 1.4 mmol) (prepared according to the procedure described forintermediate 103 in A42a-c) in CH₃OH (20 mL) at 10° C. and then themixture was stirred for 18 hours. The reaction mixture was taken up withDCM and washed with a solution of hydroxide de sodium 1M, the organiclayer was washed with water, dried over MgSO₄, filtered and evaporatedtill dryness. The residue (1.3 g) was purified by chromatography oversilica gel (Irregular, SiOH, 15-40 μm, 300 g; mobile phase from 0.5%NH₄OH, 93% DCM, 7% MeOH to 1% NH₄OH, 90% DCM, 10% MeOH). The purefractions were collected and concentrated. The residue was crystallizedfrom diethyl ether, the precipitate was filtered and dried under vacuumto give 0.11 g (19%) of compound 646. MP: 125° C. (Kofler)

Example B55 Preparation of Compound 647

as a HCl Salt

A 5N solution of HCl in i-PrOH (0.7 mL; 3.4 mmol) was added dropwise toa solution of intermediate

(0.5 g; 0.8 mmol) (prepared according to the procedure described forintermediate 105 in A42e) in CH₃OH (20 mL) at 10° C. and then themixture was stirred 18 hours. The reaction mixture was evaporated tilldryness and the residue was taken up with DCM and basified with asolution of sodium hydroxide 1N. The organic layer was washed withwater, dried (MgSO₄), filtered and evaporated till dryness. The residuewas crystallized from diethyl ether and 1 mL of HCl 3N. The precipitatewas filtered and dried to afford 0.2 g (49%) of compound 647. MP: 133°C. (Kofler)

Example B56 Preparation of Compound 655

K₂CO₃ (0.38 g; 2.7 mmol) was added to intermediate 109 (1.4 g; 2.7 mmol)in MeOH (40 mL). The solution was stirred at room temperature for 3hours. The reaction mixture was poured out into water and EtOAc wasadded. The organic layer was dried (MgSO₄), filtered and evaporated tilldryness to give 1.2 g of compound 655.

Example B57 Preparation of Compound 658

Intermediate 110 (0.4 g; 0.67 mmol) was hydrogenated at room temperaturein MeOH (20 mL) with Nickel de Raney (0.4 g; 6.88 mmol) as a catalyst inpressure vessel (3 bars). After 5 hours the catalyst was filtered off ona pad of Celite® and the filtrate was concentrated in vacuo untildryness. The resiude (0.32 g) was purified by chromatography over silicagel (Spherical SiOH, 10 μm, 60 g; mobile phase, 0.1% NH₄OH, 98% DCM, 2%MeOH). The pure fractions were collected and evaporated to dryness. Theresidue (0.19 g) was crystallized from diethyl ether. The precipitatewas filtered and dried to give 0.16 g (42%) of compound 658. MP: 152° C.(DSC).

Example B58 Preparation of Compound 659

K₂CO₃ (0.17 g, 1.19 mmol) was added to intermediate 111

(0.66 g, 1.19 mmol) (prepared according to the procedure described inA44 starting from intermediate 112) in MeOH (20 mL). The solution wasstirred at room temperature for 3 hours. The reaction mixture was pouredout into water and EtOAc was added. The organic layer was dried overMgSO₄, filtered and evaporated till dryness. The residue wascrystallized from CH₃CN and diethyl ether, the precipitate was filteredand dried to give 0.25 g (44%) of compound 659. MP: 106° C. (DSC).

Example B59 Preparation of compounds 660 and 661

NaH (0.19 g; 4.7 mmol) was added portionwise to intermediate 118 (0.95g; 2.4 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture wasstirred at 5° C. for 1 hour. Then 1,2-epoxy-3,3,3-trifluoropropane (0.4mL; 4.7 mmol) was added dropwise at 5° C. under N₂ flow. The reactionmixture was stirred at 5° C. for 1 hour, then was allowed to rise toroom temperature, stirred for 18 hours and 3 hours at 60° C. Thereaction was poured out into ice water and EtOAc was added. The organiclayer was separated, washed with brine, dried (MgSO₄), filtered and thesolvent was evaporated. The residue (1.44 g) was purified bychromatography over silica gel (Irregular, SiOH 20-45 μm, 450 g, mobilephase gradient from 0.5% NH₄OH, 98% DCM, 2% MeOH to 1% NH₄OH, 88% DCM,12% MeOH). The pure fractions were collected and evaporated to provide1.44 g of residue. The enantiomers were separated by chiral supercritical fluid chromatography (CHIRALPAK AD-H 5 μm 250×20 mm; mobilephase, 0.3% 2-propylamine, 55% CO₂, 45% MeOH). The desired productfractions were collected and the solvent was evaporated. The firsteluted enantiomer (0.15 g) was crystallized from diethyl ether. Theprecipitate was filtered and dried to afford 0.11 g (9%) of compound 660(R*, MP=154° C. (DSC)). The second eluted enantiomer (0.15 g) wascrystallized from diethyl ether. The precipitate was filtered and driedto afford 0.116 g (10%) of compound 661 (S*, MP=151° C. (DSC)).

Example B59A Preparation of Compounds 926 (Free Base) and 892 (HCl Salt)

as a HCl Salt

The following reaction was performed two times:

Sodium hydride (2.0 g, 49.8 mmol) was added portionwise to a solution ofintermediate 3 (9 g, 24.9 mmol) in DMF (140 mL) at 5° C. under N₂ flow.The reaction mixture was stirred at 5° C. for 1 hour, then1.2-epoxy-3-methylbutane (5.3 mL, 49.8 mmol) was added dropwise at 5° C.under N₂ flow. The reaction mixture was stirred 1 hour at 5° C., thenstirred at 80° C. for 3 hours. The reaction was poured out into icewater and EtOAc was added. The organic layer was separated, washed withbrine, dried (MgSO₄), filtered and the solvent was evaporated to give abrown oil. The residue was purified by chromatography over silica gel(SiOH 20-45 μm, mobile phase (0.1% NH₄OH, 97.5% DCM, 2.5% MeOH). Thedesired product fraction were collected and evaporated to provide 1.2 g(11%) of compound 389 and 3.36 g (25%) of compound 926. This laterfraction was repurified by chromatography over silica gel (SiOH 20-45 μm450 g, mobile phase 0.1% NH₄OH, 98% DCM, 2% MeOH). The product fractionwas collected and evaporated to provide 1.1 g (8%) of compound 926. Afraction (300 mg) was converted into the HCl salt in MeOH. The solid wasfiltered, washed with Et₂O and dried to give 159 mg of a red powdercompound 892.

Example B60 Preparation of Compound 664

NaH (0.11 g; 2.8 mmol) was added portionwise to intermediate 3 (0.5 g;1.4 mmol) in N, N-dimethylformamide (3 mL). The reaction mixture wasstirred at 5° C. for 1 hour. Then dimethylsulfamoyl chloride (0.3 mL;2.8 mmol) was added dropwise at 5° C. under N₂ flow. The reactionmixture was stirred at 5° C. for 1 hour, then was allowed to rise toroom temperature and stirred for 6 hours. The reaction was poured outinto ice water and EtOAc was added. The organic layer was separated,washed with brine, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (0.8 g) was purified by chromatography oversilica gel (SiOH 5 μm, 150*30 mm, mobile phase gradient from 100% DCM to0.4% NH₄OH, 96% DCM, 4% MeOH). The pure fractions were collected andevaporated. The residue (0.05 g) was crystallized from diethyl ether.The precipitate was filtered and dried to afford 0.046 g (7%) ofcompound 664. MP: 80° C. (Kofler).

Example B61 Preparation of Compound 667 and 668

A solution of intermediate 10 (1 g; 2 mmol), 3-methyl-11H-1,2,4-triazole(0.35 g, 4.2 mmol) and K₂CO₃ (0.72 g; 5.2 mmol) in1-methyl-2-pyrrolidinone (35 mL) was stirred at 15135° C. for 18 hours.The reaction mixture was cooled down to room temperature and dilutedwith EtOAc and water. The organic layer was separated, washed withwater, dried (MgSO₄), filtered and evaporated till dryness. The residue(1.8 g) was purified by chromatography over silica gel (SiOH 20-45 μm,450 g; mobile phase 0.1% NH₄OH, 97% DCM, 3% MeOH). The pure fractionswere collected and the solvent was evaporated. The residue (0.72 g) wasseparated by chiral super critical fluid chromatography (CHIRALPAK AD-H5 μm 250×20 mm; mobile phase, 0.3% 2-propylamine, 50% CO₂, 50%isopropanol). The desired product fractions were collected and thesolvent was evaporated. The first product was crystallized from diethylether. The precipitate was filtered and dried to give 0.25 g (26%) ofcompound 667. MP: 181° C. (DSC). The second product was crystallizedfrom diethyl ether. The precipitate was filtered and dried to give 0.27g (28%) of compound 668. MP: 137° C. (DSC).

Example B62 Preparation of Compound 669

The experiment has been performed 6 times on the following amounts.

A mixture of intermediate 3 (0.5 g; 1.4 mmol), diethyl(vinyl)phosphonate(0.5 mL; 3 mmol) and tri-N-butylphosphine (0.035 mL; 0.1 mmol) in CH₃CN(2 mL) was stirred at 140° C. for 15 hours in a sealed tube. Thereaction mixture was cooled down to room temperature and diluted withDCM and water. The organic layers were separated, combined, dried(MgSO₄), filtered and evaporated till dryness. The residue (7 g) waspurified by chromatography over silica gel (SiOH 20-45 μm, 450 g; mobilephase 0.1% NH₄OH, 95% DCM, 5% iPrOH). The pure fractions were collected,the solvent was evaporated. The residue (3.1 g) was crystallized fromCH₃CN and diethyl ether, the precipitate was filtered off and dried togive 0.88 g (21%) of compound 669. MP: 122° C. (DSC).

Example B63 Preparation of Compound 693

as a HCl Salt

Trifluoroacetic acid (7 mL; 94.7 mmol) was added to a solution of

prepared according to a protocol as described in B3B (1.2 g; 2 mmol) inDCM (60 mL). Then the solution was stirred at room temperature for 2hours. The reaction mixture was poured out into ice water and basifiedwith NH₄OH. The product was extracted with DCM. The organic layer wasdried (MgSO₄), filtered and the solvent was evaporated. The residue wascrystallized from diethyl ether and the precipitate was filtered off.

The precipitate was dissolved in isopropyl alcohol and stirred at 0° C.,then 0.8 mL of HCl i-PrOH 5N was added dropwise. Diethyl ether was addedand the solution was stirred at 0° C. for 1 hour. The precipitate wasfiltered and dried to afford 0.48 g (35%) of compound 693 MP: 151° C.(DSC).

Example B64 Preparation of Compound 846

Lithium hydroxide monohydrate (0.085 g; 2.0 mmol) was added portionwiseto a solution of intermediate 142 (0.72 g; 1.4 mmol) in THF (20 mL) andH₂O (6 mL) at room temperature. The reaction mixture was stirred at 70°C. for 24 hours. The reaction mixture was evaporated until dryness. Theresidue was taken up with diethyl ether. The precipitate was filteredoff and dried under vacuum, yielding 0.577 g (88%) of compound 846. MP:170° C. (Kofler)

Example B65 Preparation of Compound 763

Reaction performed in a microwave device (biotage) in a sealed tube.

Intermediate 88a (198.6 mg, 0.552 mmol), intermediate 131 (520 mg, 1.21mmol) and tetrakis(triphenylphosphine)palladium (0) (31.89 mg, 0.028mmol) in toluene (2.6 ml) were stirred at 160° C. for 40 minutes.Toluene (2.6 ml) was added and the reaction mixture was stirred at 160°C. for 40 minutes. Water was added and the reaction mixture wasextracted with AcOEt. The organic layer was dried (MgSO₄), filtered anddried to give a yellow oil. This oil was crystallized from CH₃CN. Thecrystals were dried (room temperature) to give compound 763 as a yellowpowder. MP: 176° C.

C. Conversion Reactions Conversion 1 Preparation of Compound 44a

and Compound 44.

HCl

HCl (5.53 mL; 27.65 mmol) was added to a solution of compound 6 (3.2 g;5.53 mmol) in CH₃OH (70 mL) and heated to 60° C. for 8 hours. Thereaction mixture was cooled to room temperature, poured into H₂O,basified with K₂CO₃ and extracted with EtOAc. The organic layer wasdried (MgSO₄), filtered and evaporated to dryness. The residue waspurified by chromatography over silica gel (Irregular SiOH, 15-40 μm 30g MERCK; mobile phase, gradient 100% DCM to 90% DCM, 10% MeOH, 0.1%NH₄OH). The desired fraction was collected and the solvent wasevaporated. The compound 44a 1.95 g (71%) was dissolved in diisopropylalcohol and HCl (5 to 6N in alcohol) (3 mL), stirred for 30 minutes andevaporated to dryness. The residue was crystallized in diethyl ether,yielding 1.537 g (47%) of compound 44. MP=215.29° C. (DSC).

Conversion 2 Preparation of Compound 45

Compound 9 (3.02 g; 5.95 mmol) in pyrrolidine (50 mL) was heated at 70°C. for 2 hours. The reaction mixture was cooled to room temperature andevaporated to dryness. The residue was poured into H₂O and extractedwith EtOAc. The organic layer was dried (MgSO₄), filtered and evaporatedto dryness. The residue (4.04 g) was purified by chromatography oversilica gel (Irregular SiOH, 15-40 μm, 90 g; mobile phase, gradient from100% DCM to 90% DCM/10% MeOH/0.1% NH₄OH). The desired fractions werecollected and the solvent was evaporated, yielding 1.83 g (57%) ofcompound 45.

Conversion 2A Preparation of Compound 344

as a HCl Salt

A solution of compound 310 (0.93 g; 2.1 mmol), pyrrolidine (0.52 mL; 6.4mL), K₂CO₃ (0.3 g; 2.2 mmol) in CH₃CN (50 mL) was stirred at 80° C. for24 hours. The reaction mixture was cooled down to room temperature,poured out into ice water and extracted with EtOAc. The organic layerwas separated and washed with water, dried (MgSO₄), filtered and thesolvent was evaporated. The residue (0.9 g) was purified bychromatography over silica gel (SiOH, 5 μm; mobile phase gradient from0.2% NH₄OH, 98% DCM, 2% MeOH to 1.3% NH₄OH, 87% DCM, 13% MeOH). The purefractions were collected and concentrated. The residue (0.52 g) wasdissolved in MeOH and converted into the hydrochloric acid salt withHCl/2-propanol. Et₂O was added and the precipitate was stirred for 30minutes, filtered off and dried to afford 0.55 g (47%) of compound 344.MP: 162° C. (DSC)

Conversion 2B Preparation of Compound 692 and 563

as a HCl salt

as a HCl Salt

NaH (0.13 g; 3.3 mmol) was added portionwise to 2,4-dimethylimidazole(0.3 g; 3 mmol) in N,N-dimethylformamide (25 mL) at 5° C. under N₂ flow.The reaction mixture was stirred at 5° C. for 30 minutes, then compound236 (1 g; 2.4 mmol) was added at 5° C. under N₂ flow. The reactionmixture was allowed to warm to room temperature and stirred for 18hours. The reaction was poured out into ice water. The organic layer wasseparated and washed with water, dried (MgSO₄), filtered and the solventwas evaporated. The residue (1.8 g) was purified by chromatography oversilica gel (SiOH, 15-40 μm, 300 g; mobile phase 0.5% NH₄OH, 95% DCM, 5%MeOH). The pure fractions were collected and concentrated. The residue(1 g) was purified by achiral super critical fluid chromatography (Amino6 μm; mobile phase 0.3% isopropylamine, 15% MeOH, 85% CO₂). The purefractions were collected and the solvent was evaporated till dryness.The first fraction (0.44 g) was further purified by chromatography oversilica gel (SiOH, 5 μm; mobile phase gradient from 0.4% NH₄OH, 96% DCM,4% MeOH to 1.5% NH₄OH, 85% DCM, 15% MeOH). The pure fractions werecollected and concentrated. The residue (0.38 g) was dissolved inacetone, then HCl 4N in dioxane was added dropwise. Diethyl ether wasadded and the precipitate was filtered and dried to afford 0.39 g (27%)of compound 692. MP: 157° C. (DSC).

The second fraction was dissolved in CH₃CN, then HCl 4N in dioxane wasadded dropwise. The precipitate was filtered and dried to afford 0.11 g(8%) of compound 563. MP: 201° C. (DSC).

can be prepared according to the above protocol.

Conversion 3 Preparation of Compound 46

Hydrazine monohydrate (0.15 mL; 4.8 mmol) was added to a solution ofcompound 47 (0.420 g; 0.7 mmol) in EtOH (20 mL). The mixture was heatedat 80° C. for 24 hours. The mixture was cooled to room temperature,evaporated and the residue was poured into water. The organic layer wasextracted with DCM, washed with brine, dried (MgSO₄), filtered andevaporated to dryness. The crude product was purified by chromatographyover silica gel (Sunfire Silica 5 μm 150×30.0 mm; mobile phase, gradientfrom 0% NH₄OH, 100% DCM, 0% MeOH to 0.8% NH₄OH, 92% DCM, 8% MeOH). Thepure fractions were collected and the solvent was evaporated tilldryness, yielding 56 mg (71%) of compound 46.

Conversion 4 Preparation of Compound 48

Methanesulfonyl chloride (0.093 mL, 1.2 mmol) was added to a solution ofcompound 93 (250 mg, 0.6 mmol) and Et₃N (0.25 mL, 1.8 mmol) in DCM (10mL) at 5° C. The mixture was stirred at room temperature for 24 hours.The reaction was poured out into ice water and DCM was added. Theorganic layer was separated, washed with brine, dried (MgSO₄), filteredand the solvent was evaporated. The crude product was crystallized fromdiethyl ether. The precipitate was filtered and dried under vacuum togive 118 mg (40%) of compound 48. MP=189° C. (DSC).

Conversion 5 a) Preparation of Compound 50

NaH (44.8 mg, 1.12 mmol) was added portionwise to a solution of compound17 (0.3 g, 0.75 mmol) in DMF (5 mL) at 5° C. under N₂. The reactionmixture was stirred for 30 minutes, then 1,2-dibromoethane (0.194 mL,2.24 mmol) was added dropwise. The reaction mixture was stirred at roomtemperature for 5 hours, then poured into H₂O/K₂CO₃ and extracted withEtOAc. The organic layer was dried (MgSO₄), filtered and evaporated todryness. The residue was purified by chromatography over silica gel(Irregular SiOH, 15-40 μm MERCK; mobile phase, gradient 100% DCM to 97%DCM, 3% MeOH, 0.1% NH₄OH). The pure fractions were collected andevaporated to dryness, yielding 0.236 g (63%) of compound 50.

b) Preparation of Compound 52

Compound 17 (214 mg; 0.53 mmol), 1-chloro-2-methyl-2-propanol (0.13 mL;1.28 mmol), K₂CO₃ (147 mg; 1.1 mmol) in DMF (9 mL) were heated to 120°C. for 72 hours. The reaction mixture was cooled to room temperature,poured into H₂O/K₂CO₃ and extracted with EtOAc. The organic layer wasdried (MgSO₄), filtered and evaporated to dryness. The residue (277 mg)was purified by chromatography over silica gel (Irregular SiOH, 15-40μm, 30 g; mobile phase, gradient from 100% DCM to 90% DCM, 10% MeOH,0.1% NH₄OH) The pure fractions were collected and evaporated to dryness.The residue (226 mg) was crystallized in diethyl ether, yielding 178 mg(90%) of compound 52. MP=159° C. (DSC).

c) Preparation of Compound 53

A mixture of compound 54(130 mg; 0.38 mmol), iodomethane (23.7 μl; 0.38mmol) and K₂CO₃ (105.3 mg; 0.76 mmol) in CH₃CN (10 mL) was refluxedovernight. More iodomethane (23.7 μl; 0.38 mmol) and K₂CO₃ (105.3 mg;0.76 mmol) were added and the reaction mixture was refluxed 8 morehours. The reaction mixture was poured onto water and the product wasextracted with EtOAc. The organic layer was washed with brine, dried(MgSO₄), filtered off and the solvent was evaporated. The residue waspurified by chromatography over silica gel (Irregular SiOH, 15-40 μm, 30g; mobile phase, 0.1% NH₄OH, 98% DCM, 2% MeOH). The pure fractions werecollected and the solvent was evaporated till dryness. The residue wascrystallized in diethyl ether, filtered and dried, yielding 29 mg (21%)of compound 53.

d) Preparation of Compound 55

NaH (0.59 g, 1.495 mmol) was added portionwise to a solution of compound17 (0.3 g, 0.75 mmol) in DMF (6 mL). The mixture was stirred at 0° C.for 1 hour, then 1-(2-oxiranylmethyl)-piperidine (0.316 mg, 2.24 mmol)was added. The resulting mixture was stirred at 5° C. for 1 hour and at90° C. overnight. The mixture was poured out into water and extractedwith DCM. The organic layer was dried, filtered and concentrated tilldryness. The residue was purified by chromatography over silica gel(Spherical SiOH, 10 μm, 60 g PharmPrep MERCK; mobile phase, 0.7% NH₄OH,93% DCM, 7% MeOH). The pure fractions were collected and the solvent wasevaporated). The pure fractions were collected and the solvent wasevaporated, yielding 0.045 g (11%) of compound 55.

e) Preparation of Compound 56

NaH (179.3 mg, 4.5 mmol) was added portionwise to a solution of compound17 (1.5 g, 3.7 mmol) in DMF (20 mL). The mixture was stirred at 0° C.for 1 hour, then (2-bromoethoxy)-tert-butyldimethylsilane (0.96 mL, 04.5mmol) was added. The resulting mixture was stirred at room temperaturefor 4 hours. The mixture was poured out into water and extracted withDCM. The organic layer was dried, filtered and concentrated till drynessto give 2.1 g of a crude residue. Tetrabutylammonium fluoride (3.75 mL,1M solution in THF, 3.75 mmol) was added dropwise to a solution of theabove residue in THF (25 mL) at room temperature and stirred at roomtemperature for 5 hours. The reaction mixture was poured out into icewater, basified with K₂CO₃ and extracted by EtOAc. The organic layer wasseparated, washed with brine, dried (MgSO₄), filtered and concentratedtill dryness. The residue was purified by chromatography over silica gel(Irregular SiOH, 15-40 μm 50 g; mobile phase, gradient 100% DCM to 97%DCM, 3% MeOH, 0.1% NH₄OH). The desired product fractions were collectedand the solvent was evaporated, yielding 1.3 g (77%) of compound 56which was triturated in Et₂O, filtered and dried under vacuum at 60° C.to give 1.22 g (73%) of compound 56. MP=147.5° C. (DSC).

f) Preparation of Compound 57

Compound 16 (0.02 g, 0.046 mmol), methyl vinyl sulfone (33 μL, 0.4mmol), Et₃N (15.5 mL, 0.11 mmol) in CH₃OH (2 mL) were heated to 120° C.under microwave irradiation for 30 minutes. The mixture was evaporatedto dryness and purified by chromatography over silica gel (IrregularSiOH, 15-40 μm, 30 g; mobile phase 95% DCM, 5% MeOH, 0.5% NH₄OH). Thedesired fractions were collected and the solvent was evaporated,yielding 22.3 mg (90%) of compound 57. MP=80° C. (Kofler).

g) Preparation of Compound 58

Dimethylsulfamoylchloride (0.06 mL, 0.56 mmol) was added dropwise to asolution of compound 17 (0.15 g, 0.37 mmol), 4-methylaminopyridine(0.0045 g, 0.037 mmol), Et₃N (0.104 mL, 0.75 mmol) in DCM (5 mL) at 5°C. under N₂ flow. The reaction mixture was stirred at 5° C. for 1 hour,then overnight at room temperature. The reaction mixture was poured outinto ice water and DCM was added. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue waspurified by chromatography over silica gel (Irregular SiOH, 15/40 μm, 30g MERCK; mobile phase, gradient 100% DCM to 97% DCM, 3% MeOH). Thedesired fractions were collected and the solvent was evaporated. Thecompound was crystallized from diethyl ether, filtered and dried undervacuum at 60° C., yielding 0.065 g (34%) of compound 58. MP=163° C.(DSC).

h) Preparation of Compound 59

Compound 60 (prepared according to conversion 7 reaction from compound127) (0.073 g, 0.15 mmol) was dissolved in DCM (5 mL),N,N-diisopropylethylamine (0.037 mL, 0.23 mmol) was added. To thissolution, methanesulfonylchloride (0.035 mL, 0.23 mmol) was addeddropwise at 0° C. and the mixture was stirred overnight. Water and DCMwere added. The organic layer was extracted with DCM. The organic layerwas dried, filtered and concentrated. The residue (0.1 g) was purifiedby chromatography over silica gel (Irregular SiOH, 15-40 μm, 30 g MERCK;mobile phase, 98% DCM, 2% MeOH). The pure fractions were collected andthe solvent was evaporated. The residue (0.089 g) was crystallized fromDIPE. The precipitate was filtered, dried under vacuum, yielding 0.04 g(47%) of compound 59. MP=200° C. (Kofler).

i) Preparation of Compound 51

NaH (0.25 mmol) was added portionwise to a solution of compound 17(0.125 mmol) in DMF (4 mL). The mixture was stirred at 5° C. for 30minutes, then allyl bromide (0.19 mmol) was added. The resulting mixturewas stirred at room temperature for 2 hours. The mixture was poured intowater and the product was extracted with EtOAc. The organic layer waswashed with water, brine, dried (MgSO₄), filtered and evaporated tilldryness, yielding 60 mg (100%) of compound 51.

Conversion 6 Preparation of Compound 61

Compound 50 (0.319 g, 0.63 mmol), K₂CO₃ (0.347 g, 2.51 mmol),methylamine in 2M THF (0.94 mL, 1.88 mmol) in CH₃CN (25 mL) were heatedat 80° C. for 15 hours. The mixture was cooled to room temperature,poured into H₂O/K₂CO₃ and extracted with EtOAc. The organic layer wasdried (MgSO₄), filtered and evaporated to dryness. The residue waspurified by chromatography over silica gel (Spherical SiOH, 10 μm, 60 gPharmPrep MERCK; mobile phase, gradient from 0.2% NH₄OH, 95% DCM, 5%MeOH to 0.2% NH₄OH, 90% DCM, 10% MeOH). The pure fractions werecollected and evaporated to dryness. The product was crystallized withDIPE and pentane, filtered and dried, yielding 157 mg (55%) of compound61. MP=103° C. (DSC).

Conversion 7 Preparation of Compound 62

Compound 63 (0.280 g, 0.46 mmol), 3N HCl (4 mL) and dioxane (4 mL) wereheated to 60° C. for 5 hours. The mixture was cooled to roomtemperature, poured into H₂O and basified with K₂CO₃. The product wasextracted with EtOAc, dried (MgSO₄), filtered and evaporated to dryness.The residue was crystallized with DIPE and diethyl ether, filtered anddried, yielding 100 mg (43%) of compound 62. MP=221° C. (DSC).

Conversion 8 Preparation of Compound 64

Lithium hydroxide monohydrate (43 mg; 1.0 mmol) was added portionwise toa solution of compound 65 (230 mg; 0.5 mmol) in THF (5 mL) and H₂O (2mL) at room temperature. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was evaporated till dryness.The residue was taken up with water and the mixture was acidified withHCl 3N. After stirring, the precipitate was filtered, washed with waterand dried under vacuum, yielding 0.206 g (88%) of compound 64.

Conversion 9 Preparation of Compound 66

A mixture of compound 67 (0.245 g, 0.53 mmol), zinc cyanide (0.093 g,0.79 mmol), Pd₂(dba)₃ (0.024 g, 0.026 mmol), Zinc (0.017 g, 0.26 mmol)and 1,1′-bis(diphenylphosphino)ferrocene (0.036 g, 0.066 mmol) inN,N-dimethylacetamide (2 mL) was heated at 140° C. for 1 hour undermicrowave irradiation. The reaction was poured out into ice water andDCM was added. The organic layer was separated, washed with brine, dried(MgSO₄), filtered and the solvent was evaporated. The residue (0.27 g)was purified by chromatography over silica gel (Irregular SiOH, 15-40μm, 30 g MERCK; mobile phase, gradient from 98% DCM, 2% MeOH to 94% DCM,6% MeOH). The pure fractions were collected and the solvent wasevaporated. The residue (0.2 g, 92%) was crystallized from DIPE. Theprecipitate was filtered, dried under vacuum, yielding 0.046 g (21%) ofcompound 66. MP=143° C.

Conversion 10 Preparation of Compound 68

as a HCl Salt

A solution of compound 66 (0.1 g, 0.24 mmol) and Nickel (0.1 g, 1.70mmol) in ammonia and MeOH (4 mL of a 7N solution) was hydrogenated under2 atmospheres of H₂ for 3 hours at room temperature, using Nickel as thecatalyst. The catalyst was removed by filtration through celite, washedwith DCM and the filtrate was concentrated. The residue (0.1 g) waspurified by chromatography over silica gel (Irregular SiOH, 15-40 μm, 30g MERCK; mobile phase gradient from 98% DCM, 2% MeOH to 94% DCM, 6%MeOH). The pure fractions were collected and the solvent was evaporated.The residue (0.075 g, 74%) was dissolved in iPrOH, 0.11 mL of HCl5N/iPrOH was added dropwise at 5° C. The salt was filtered, washed withDIPE and dried under vacumn at 60° C., yielding 0.032 g (29%) ofcompound 68.

Conversion 11 Preparation of Compound 69

A mixture of compound 64 (Li-salt) (500 mg, 1.18 mmol),1,1,1-trimethyl-N-(trimethylsilyl)silanamine (0.5 mL, 2.35 mmol),N3-(ethylcarbonimidoyl)-N1,N1-dimethyl-1,3-propanediamine hydrochloride(1:1) (365 mg, 2.35 mmol), HOBt (318 mg, 2.35 mmol), Et₃N (0.33 mL, 2.35mmol) in DMF (80 mL) was stirred at room temperature overnight. Themixture was poured out into ice water and EtOAc was added. The organiclayer was separated, washed with brine, dried (MgSO₄), filtered and thesolvent was evaporated to dryness. The residue (167 mg) was trituratedfrom diethyl ether, filtered and dried under vacuum to give 141 mg (29%)of compound 69. MP=264° C. (DSC).

Conversion 12 Preparation of Compound 70

as a HCl Salt

HCl (0.496 mL; 2.5 mmol) was added dropwise to a solution of compound 71(277 mg; 0.50 mmol) in isopropyl alcohol (20 mL). The reaction mixturewas heated at 50° C. for 4 hours, then 70° C. for 4 hours. The mixturewas poured into H₂O and basified with K₂CO₃, then extracted with EtOAc.The organic layer was dried (MgSO₄), filtered and evaporated to dryness.The residue was purified by chromatography over silica gel (IrregularSiOH, 15-40 μm, MERCK; mobile phase, gradient 100% DCM to 80% DCM, 20%MeOH, 0.1% NH₄OH). The product fractions were collected and the solventwas evaporated. The residue (110 mg) was dissolved in diisopropylalcohol and HCl (0.2 mL of a 5 to 6N in isopropyl alcohol) was added.The mixture was stirred for 30 minutes and evaporated to dryness. Thenthe residue was crystallized in diethyl ether, yielding 110 mg (39%) ofcompound 70. M.P=163° C. (DSC).

Conversion 13 Preparation of Compound 72

Formaldehyde (0.045 mL, 0.60 mmol) was added to a solution of compound73 (prepared according to conversion 7 reaction from compound 128) (0.15g, 0.30 mmol) in MeOH (2 mL) and THF (2 mL) at room temperature. Thensodium cyanoborohydride (0.028 g, 0.45 mmol) was added and the mixturewas stirred at room temperature for 1 hour. The mixture was poured outinto ice. The organic layer was extracted with DCM, dried (MgSO₄),filtered off and evaporated till dryness. The residue (0.1 g) waspurified by chromatography over silica gel (Irregular SiOH, 15-40 μm, 30g MERCK; mobile phase, gradientfrom 95% DCM, 5% MeOH to 80% DCM, 20%MeOH). The pure fractions were collected and the solvent was evaporated.The residue (60 mg, 39%) was crystallized from DIPE/diethyl ether. Theprecipitate was filtered, dried under vacuum, yielding 0.046 g (30%) ofcompound 72. MP=120° C. (Kofler).

Conversion 14 Preparation of Compound 74

A mixture of compound 64 (0.14 g, 0.33 mmol), methylamine hydrochloride(0.052 g, 1.67 mmol),N3-(ethylcarbonimidoyl)-N1,N1-dimethyl-1,3-propanediamine hydrochloride(1:1) (0.077 g, 0.50 mmol), 1-hydroxybenzotriazole (0.068 g, 0.50 mmol),triethylamine (0.325 mL, 2.34 mmol) in DCM (14 mL) was stirred at roomtemperature overnight. The reaction mixture was poured out into icewater and DCM was added. The organic layer was separated, washed withbrine, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue was purified by chromatography over silica gel (Stability Silica5 μm 150×30.0 mm; mobile phase, gradient from 0% NH₄OH, 100% DCM, 0%MeOH to 0.7% NH₄OH, 93% DCM, 7% MeOH). The product fraction wascollected and the solvent was evaporated. The residue was trituratedfrom diethyl ether, filtered and dried under vacuum at 60° C., yielding0.078 g (54%) of compound 74. MP=252-254° C. (Kofler).

Conversion 15 Preparation of Compound 75

Trifluoroacetic acid (1.07 mL; 14.37 mmol) was added to a solution ofcompound 76 (2 g; 4.79 mmol) in H₂O (19.5 mL) and dioxane (80 mL). Thereaction mixture was heated to reflux for 5 hours, poured into H₂O andbasified with K₂CO₃, extracted with EtOAc. The organic layer was dried(MgSO₄), filtered and evaporated to dryness. The residue was purified bychromatography over silica gel (Irregular SiOH, 35-40 μm, 80 g GraceResolv; mobile phase, gradient 100% DCM to 90% DCM, 10% MeOH, 0.1%NH₄OH). The product fraction was collected and the solvent wasevaporated. The residue (2.1 g) was crystallized in Et₂O and CH₃CN,yielding 1.61 g (77%) of compound 75. MP=187° C. (DSC).

Conversion 16 Preparation of Compound 75

At 0° C., potassium permanganate (0.11 g, 0.7 mol) was added to asolution of compound 121 (0.28 g, 0.0007 mol) in acetone (8 mL)/H₂O (2.5mL). The solution was stirred at room temperature for 4 hours and thenpoured into ice water. DCM was added and the mixture was filteredthrough a celite layer. The organic layer was extracted, dried (MgSO₄)and evaporated to dryness. The residue (200 mg) was purified bychromatography over silica gel (Stability Silica 5 μm 150×30.0 mm;mobile phase gradient from 0.2% NH₄OH, 98% DCM, 2% MeOH to 1.1% NH₄OH,89% DCM, 11% MeOH). The pure fractions were collected and the solventwas evaporated. The residue (100 mg, 33%) was crystallized fromCH₃CN/diethyl ether, yielding 77 mg (25%) of compound 75. MP=186° C.(DSC).

Conversion 17 Preparation of Compound 78

Iodomethane (0.5 mL, 8.0 mmol) was added very slowly to a suspension ofMg (0.196 g, 8.0 mmol) in diethyl ether (2 mL) at room temperature underN₂. When the Grignard reagent was started, diethyl ether (10 mL) wasadded and the reaction was stirred for 30 minutes. This mixture wasadded dropwise to a solution of compound 65 (0.240 g, 0.54 mmol) in THF(12 mL) at room temperature under N₂. The reaction mixture was refluxedfor 2 hours, then cooled to room temperature. The mixture was pouredinto H₂O/NH₄Cl and extracted with EtOAc. The organic layer was dried(MgSO₄), filtered and evaporated to dryness to afford a crude residue(0.248 g) which was purified by super critical fluid chromatography(CYANO 6 μm 150×21.1 mm; mobile phase, 0.3% isopropylamine, 7% MeOH, 93%CO₂). The pure fractions were evaporated yielding 90 mg of compound 78which was crystallized in Et₂O to afford 57 mg (24%) of compound 78.MP=162° C. (DSC).

Conversion 18 Preparation of Compound 79a

and Compound 79

as a HCl Salt

A mixture of compound 76 (0.505 gg; 1.21 mmol) and methylamine in 2M THF(6.05 mLmL, 12.1 mmol) in DMF (8 mL) was heated at 100° C. for 15 hoursin a sealed vessel, cooled to room temperature and poured into H₂OandK₂CO₃, extracted with EtOAc. The organic layer was dried (MgSO₄),filtered and evaporated to dryness. The residue was purified bychromatography over silica gel (Irregular SiOH, 15-40 μm 30 g MERCK;mobile phase, gradient from 100% DCM to 90% DCM, 10% MeOH, 0.1% NH₄OH).The pure fractions were evaporated yielding 0.406 g (75%) of compound79a which was dissolved in diisopropyl alcohol. HCl (5 to 6N) was added.The mixture was stirred for 30 minutes, evaporated to dryness. Then theresidue was crystallized in Et₂O, yielding 0.4 g (62%) of compound 79.MP=224° C. (DSC).

Conversion 19 Preparation of Compound 80

(E-Isomer) and Compound 81

(Z-Isomer)

Hydroxylamine hydrochloride (0.043 g, 0.62 mmol) was added to a solutionof compound 82 (0.13 g, 0.31 mmol) and pyridine (0.13 mL) in EtOH (4 mL)at room temperature. The mixture was stirred at room temperatureovernight. The reaction was poured out into ice water and EtOAc wasadded. The organic layer was separated, washed with brine, dried(MgSO₄), filtered and the solvent was evaporated. The residue waspurified by chromatography over silica gel (Spherical SiOH, 10 μm, 60 gPharmPrep MERCK; mobile phase, 0.1% NH₄OH, 98% DCM, 2% MeOH). Twodifferent residues were collected and the solvent was evaporated foreach of them. The first residue was crystallized from DIPE/CH₃CN(90/10). The precipitate was filtered and dried under vacuum, yielding0.087 g (64%) of compound 80 (E-isomer). MP=144° C. (Kofler).

The second residue (0.068 g) was crystallized from DIPE/CH₃CN (90/10).The precipitate was filtered and dried under vacuum, yielding 0.051 g(38%) of compound 81 (Z-isomer). MP=199° C. (Kofler).

Conversion 20 Preparation of Compound 83

N3-(ethylcarbonimidoyl)-N1,N1-dimethyl-1,3-propanediamine hydrochloride(1:1) (129 mg; 0.83 mmol) was added to a solution of compound 84 (223mg; 0.55 mmol), 1-methyl-3-piperidinecarboxylic acid hydrochloride (1:1)(148.8 mg; 0.82 mmol), 1-hydroxybenzotriazole (112 mg; 0.615 mmol),4-methylporpholine (182 μl; 1.66 mmol) in DMF (8 mL) at roomtemperature. The reaction mixture was stirred for 24 hours, then pouredinto H₂O/K₂CO₃ and extracted with EtOAc. The organic layer was dried(MgSO₄), filtered and evaporated to dryness. The residue was purified bychromatography over silica gel (Spherical SiOH, 10 μm, 60 g PharmPrepMERCK; mobile phase, 0.5% NH₄OH, 97% DCM, 3% MeOH). The productfractions were collected and the solvent was evaporated. The residue wascrystallized in diethyl ether, yielding 122 mg (42%) of compound 83. MP142° C. (DSC).

Conversion 21 Preparation of Compound 8

At 0° C., under N₂, diethylaminosulfur trifluoride (0.224 mL, 1.68 mmol)in DCM (2 mL) was added dropwise to a solution of compound 56 (0.250 g,0.56 mmol) in DCM (4 mL). The mixture was stirred overnight at roomtemperature. An aqueous solution of K₂CO₃ (10%) was added. The mixturewas extracted with DCM. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue (246 mg) waspurified by chromatography over silica gel (Sunfire Silica 5 μm 150×30.0mm; mobile phase, gradient from 0% NH₄OH, 100% DCM, 0% MeOH to 0.3%NH₄OH, 97% DCM, 3% MeOH). The pure fractions were collected andevaporated to dryness. The residue (58 mg) was crystallized with DIPE,filtered and dried, yielding 36 mg (14%) of compound 85.

Conversion 22 Preparation of Compound 86

A mixture of compound 122 (0.5 g, 1.21 mmol), sodium azide (0.235 g,3.62 mmol), ammonium chloride (194 mg; 3.62 mmol) inN,N-dimethylformamide (10 mL) was heated at 140° C. for 72 hours. Thereaction mixture was cooled to room temperature and poured out into icewater. EtOAc was added and the organic layer was separated. The aqueouslayer was acidified with HCl 3N. EtOAc was added and the mixture wasstirred. The organic layer was separated, dried (MgSO₄), filtered andthe solvent was evaporated. The residue (0.42 g) was purified bychromatography over silica gel (Spherical SiOH, 10 μm, 60 g PharmPrepMERCK; mobile phase, 93% DCM, 7% MeOH). The product fractions werecollected and the solvent was evaporated. The residue (0.110 g, 20%) wascrystallized from diethyl ether/CH₃CN, filtered and dried under vacuumat 60° C., yielding 0.070 g (12%) of compound 86. MP=196° C. (DSC).

Conversion 23 Preparation of Compound 87

Diethylaminosulfur trifluoride (276p1; 2.25 mmol) was added dropwise toa solution of compound 88 (550 mg; 1.12 mmol) in DCM (14 mL) at 0° C.The reaction mixture was stirred at room temperature for 2 hours and wasthen poured into H₂O/K₂CO₃. The organic layer was extracted, dried(MgSO₄), filtered and evaporated to dryness. The residue (629 mg) waspurified by chromatography over silica gel (Spherical SiOH, 10 μm, 60 gPharmPrep MERCK; mobile phase, 0.5% NH₄OH, 97% DCM, 3% MeOH). Theproduct fractions were collected and the solvent was evaporated. Theresidue (100 mg) was purified by achiral super critical fluidchromatography on (2 ETHYLPYRIDINE 6 μm 150×21.2 mm; mobile phase, 0.3%2-propylamine, 87% CO₂, 13% MeOH). The product fractions were collectedand the solvent was evaporated. The residue (0.08 g) was crystallized inEt₂O yielding 72 mg (15%) of compound 87.

Conversion 24 Preparation of Compound 89

LiAlH₄ (0.031 g, 0.82 mmol) was added portionwise to a mixture ofcompound 90 (0.2 g, 0.41 mmol) in THF (10 mL) at 5° C. under N₂. Themixture was stirred at 5° C. for 3 hours. EtOAc followed by H₂O wasadded dropwise to the mixture at −5° C. The suspension was passedthrough a short pad of celite. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue waspurified by chromatography over silica gel (Sunfire Silica 5 μm 150×30.0mm; mobile phase, gradient from 0% NH₄OH, 100% DCM, 0% MeOH to 0.8%NH₄OH, 92% DCM, 8% MeOH). The pure fractions were collected and thesolvent was evaporated. The residue was crystallized from DIPE. Theprecipitate was filtered and dried under vacuum, yielding 73 mg (40%) ofcompound 89. MP=126° C. (DSC).

Conversion 25 Preparation of Compound 91

Copper(I) iodide (52.697 mg, 0.28 mmol), then N,N-diisopropylethylamine(0.829 mL, 4.75 mmol) were added at 5° C. to a solution of compound 38(1.105 g, 2.78 mmol) and ethyl azidoacetate (1.38 mL, 5.53 mmol) in THF(35 mL). The reaction mixture was stirred at room temperature for 18hours. The mixture was quenched with water and extracted with EtOAc. Theorganic layer was decanted, dried (MgSO₄), filtered and evaporated todryness. The residue was purified by chromatography over silica gel(Irregular SiOH, 15-40 μm, 300 g MERCK; mobile phase, 0.1% NH₄OH, 97%DCM, 3% MeOH). The fractions were collected yielding 430 mg of residuewhich was furtherpurified by achiral super critical fluid chromatographyon (AMINO 6 μm 150×21.2 mm; mobile phase, 0.3% 2-propylamine, 90% CO₂,10% MeOH). The pure fractions were collected and evaporated to drynessyielding two fractions.

The first fraction (90 mg) was crystallized from CH₃CN/DiPE. Theprecipitate was filtered off and dried yielding 74 mg (5%) of compound91, MP=88° C. (DSC). The second fraction yielded 360 mg (25%) ofcompound 91.

Conversion 26 Preparation of Compound 92

Compound 93 (740 mg, 1.77 mmol), Et₃N (0.54 mL, 3.89 mmol) andtrifluoroacetic anhydride (0.37 mL, 2.65 mmol) in THF (25 mL) werestirred at room temperature overnight. The reaction mixture was pouredinto water and extracted with DCM. The organic layer was washed with anaqueous solution of K₂CO₃(10%), then with water, then dried (MgSO₄),filtered and evaporated to dryness. The residue (800 mg) was purified bychromatography over silica gel (Irregular SiOH, 15-40 μm, 30 g; mobilephase, 0.2% NH₄OH, 98% DCM, 2% MeOH). The product fractions werecollected and the solvent was evaporated. The residue (730 mg) wascrystallized from diethyl ether/DIPE to give 465 mg (51%) of compound92. MP=139° C. (DSC).

Conversion 27 Preparation of Compound 300

A suspension of compound 38 (1.38 g; 3.46 mmol),2-iodo-1-methyl-1H-imidazole (0.45 g; 2.16 mmol) and Et₃N (3.0 mL; 21.6mmol) in DMSO (25 mL) was degassed under N₂.Dichlorobis(triphenylphosphine)-palladium (304 mg; 0.43 mmol) andcopper(I) iodide (41 mg; 0.22 mmol) were added and the reaction mixturewas stirred at 90° C. for 1.5 hours. The reaction mixture was cooled toroom temperature, poured onto waterand extracted with EtOAc. The organiclayer was decanted, washed with brine, dried (MgSO₄), filtered andevaporated to dryness. The residue was purified by chromatography oversilica gel (Irregular SiOH, 15-40 μm, 300 g MERCK; mobile phase, 0.4%NH₄OH, 96% DCM, 4% MeOH). The pure fractions were collected andevaporated to dryness. The residue (780 mg) was then purified by achiralsuper critical fluid chromatography on (2 AMINO 6 μm 150×21.2 mm; mobilephase, 0.3% 2-propylamine, 80% CO₂, 20% MeOH). The pure fractions werecollected and evaporated to dryness, yielding 430 mg (41%) of compound300. This fraction was taken up with CH₃CN. The precipitate was filteredoff and dried yielding 377 mg (36%) of compound 300. MP=192° C. (DSC).

Conversion 28 Preparation of Compound 94

A mixture of compound 109 (2.5 g, 5.29 mmol) in NaOH 3M (7 mL) and THF(40 mL) was stirred at room temperature for 18 hours. The reactionmixture was quenched with a 10% solution of NH₄Cl and EtOAc was added.The pH was adjusted to 4.5 by adding HCl 3N. The organic layer wasdecanted, washed with NH₄Cl saturated, dried (MgSO₄), filtered andevaporated to dryness. The residue was crystallized from EtOH. Theprecipitate was filtered off, washed with EtOH, then diethyl ether anddried, yielding 2.02 g (86%) of compound 94. MP=101° C. (DSC).

Conversion 29 Preparation of Compound 95a

and Compound 95

as a HCl Salt

A mixture of compound 93 (0.15 g, 0.36 mmol),3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.085 g, 0.54 mmol),N3-(ethylcarbonimidoyl)-N1,N1-dimethyl-1,3-propanediamine hydrochloride(1:1) (0.083 g, 0.54 mmol), 1-hydroxybenzotriazole (0.073 g, 0.54 mmol),Et₃N (0.075 mL, 0.54 mmol) in DCM (4 mL) was stirred at room temperatureovernight. The reaction mixture was poured out into ice water and DCMwas added. The organic layer was separated, washed with brine, dried(MgSO₄), filtered and the solvent was evaporated. The residue (0.250 g)was purified by chromatography over silica gel (Spherical SiOH, 10 μm,60 g PharmPrep MERCK; mobile phase, 0.1% NH₄OH, 98% DCM, 2% MeOH). Theproduct fractions were collected and the solvent was evaporated. Thecompound 95a was dissolved in CH₃CN, cooled to 5° C. and a solution ofHCl 5N/iPrOH (0.3 mL) was added dropwise. The mixture was evaporatedtill dryness at room temperature. The mixture was taken up with diethylether, then the precipitate was filtered off and dried under vacuum at60° C., yielding 0.172 g (80%) of compound 95.

Conversion 30 Preparation of Compound 96

Acetone (0.322 mL, 4.361 mmol) was added to a solution of compound 70(0.2 g, 0.436 mmol) in MeOH (5 mL) and THF (5 mL) at room temperature.Then sodium cyanoborohydride (0.055 g, 0.872 mmol) was added and themixture was stirred at room temperature overnight. Acetone (0.129 mL,1.745 mmol) and sodium cyanoborohydride (0.055 g, 0.872 mmol) were addedand the mixture was stirred at room temperature for the weekend. Themixture was poured out into ice, then the organic layer was extractedwith DCM, dried (MgSO₄), filtered off and evaporated till dryness. Theresidue (254 mg) was purified by chromatography over silica gel(Irregular SiOH, 15-40 μm, 300 g Merck; mobile phase, gradient from 100%DCM to 90% DCM, 10% CH₃OH, 0.1% NH₄OH). The pure fractions werecollected and evaporated to dryness. The product (236 mg) wascrystallized with DIPE, filtered and dried, yielding 186 mg (85%) ofcompound 96. MP=168° C. (DSC).

Conversion 31 Preparation of Compound 97

and Compound 98

*means relative stereochemistry

The enantiomers of compound 75 (5.4 g) were separated by chiral supercritical fluid chromatography (CHIRALPAK AD-H 5 μm 250×20 mm; mobilephase, 0.3% 2-propylamine, 40% CO₂, 60% MeOH). The desired productfractions were collected and the solvent was evaporated. The firsteluted enantiomer (2.1 g) was crystallized in diethyl ether, yielding1.965 g (36%) of compound 97 (R*, MP=188° C. (DSC)). The secondenantiomer (2.1 g) was crystallized in diethyl ether, yielding 2 g (37%)of compound 98 (S*, MP=186° C. (DSC).

Conversion 32 Preparation of Compound 99

A mixture of compound 100 (0.5 g, 0.91 mmol) in HCl 4M in dioxane (2 mL)and CH₃CN (10 mL) was heated at 50° C. overnight. The mixture was pouredout into ice, basified with (10m L) was heated at 50° C. overnight. Themixture was poured out into ice, basified with K₂CO₃ and extracted withDCM. The organic layer was dried (MgSO₄), filtered and evaporated tilldryness to give 0.4 g (99%) of compound 99.

Conversion 33 Preparation of Compound 101

Sodium hydride (0.054 g, 1.36 mmol) was added portionwise to a solutionof compound 99 (0.4 g, 0.9 mmol) in DMF (4 mL) at 5° C. under N₂ flow.The reaction mixture was stirred at 5° C. for 1 hour, then iodomethane(68 μL, 1.09 mmol) was added dropwise at 5° C. under N₂ flow. Thereaction mixture was stirred for 1 hour at 5° C., then at roomtemperature overnight. The reaction was poured out into ice andextracted with EtOAc. The organic layer was washed with brine, dried(MgSO₄), filtered and evaporated till dryness. The residue (0.71 g) waspurified by chromatography over silica gel (Sunfire Silica 5 μm 150×30.0mm; mobile phase, gradient from 0.2% NH₄OH, 98% DCM, 2% MeOH to 0.8%NH₄OH, 92% DCM, 8% MeOH). The pure fractions were evaporated tilldryness. The residue was crystallized from diethyl ether and dried,yielding 0.172 g (42%) of compound 101. MP=186° C., (Kofler).

Conversion 34 Preparation of Compound 102

3,3-Bis(bromomethyl)oxetane (1.592 g, 6.52 mmol) was added to compound84 (2.2 g, 5.44 mmol) and sodium carbonate (0.961 g, 9.1 mmol) in1,4-dioxane (80 mL) at room temperature. The reaction mixture wasstirred at reflux for 7 days, then cooled to room temperature. Themixture was filtered. The filtrate was concentrated under reducedpressure. The residue was purified by chromatography over silicagel(mobile phase, gradient from 99% DCM, 1% of a solution of NH₃ in MeOH to97.5% DCM, 2.5% of a solution of NH₃ in MeOH). The pure fractions werecollected and concentrated under reduced pressure, yielding 880 mg (33%)of compound 102.

Conversion 35 Preparation of Compound 103

as a HCl Salt

Sodium cyanide (0.094 g, 1.92 mmol) was added portionwise to a solutionof compound 104 (0.5 g, 0.96 mmol) in EtOH (10 mL) and H₂O (3 mL) atroom temperature. The reaction mixture was heated at 60° C. overnight.The reaction mixture was cooled to room temperature and poured out intoice water. EtOAc was added and the solution was basified with an aqueoussolution of K₂CO₃ (10%). The organic layer was separated, washed withbrine, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (0.63 g) was purified by chromatography over silica gel(Spherical SiOH, 10 μm 60 g PharmPrep MERCK; mobile phase 0.1% NH₄OH,98% DCM, 2% MeOH). The pure fractions were collected and the solvent wasevaporated, yielding 0.37 g of compound (75%). This compound was furtherpurified by chiral super critical fluid chromatography on (CHIRALPAKAD-H 5 μm 250×20 mm; mobile phase, 0.3% 2-propylamine, 60% EtOH, 40%CO₂). The desired product fractions were collected and the solvent wasevaporated. The residue (0.240 g, 49%) was dissolved in CH₃CN and cooledat 5° C. A solution of HCl 5N/i-PrOH (0.28 mL) was added dropwise at 5°C. The solution was evaporated till dryness. The residue was trituratedwith diethyl ether, filtered and dried under vacuum at 60° C., yielding0.250 g (42%) of compound 103.

Preparation of Compound 105

as a HCl Salt

a-1) Preparation of Intermediate 63

and Compound 126

Methanesulfonyl chloride (0.18 mL; 2.31 mmol) was added dropwise to asolution of compound 108 (580 mg; 1.15 mmol), Et₃N (0.4 mL; 2.88 mmol)in DCM (10 mL) at 5° C. under N₂ flow. The reaction mixture was stirredat 5° C. for 2 hours. The reaction mixture was poured out into ice waterand DCM was added. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated, yielding 0.65 g (97%) ofintermediate 63 and compound 126.

a-2) Sodium cyanide (0.110 g, 2.24 mmol) was added portionwise to asolution of intermediate 63 (0.65 g, 1.12 mmol) in EtOH (10 mL) and H₂O(3 mL) at room temperature. The reaction mixture was heated at 60° C.overnight. The reaction mixture was cooled to room temperature andpoured out into ice water. EtOAc was added and the solution was basifiedwith an aqueous solution of K₂CO₃ (10%). The organic layer wasseparated, washed with brine, dried (MgSO₄), filtered and the solventwas evaporated. The residue (was purified by chromatography over silicagel (Sunfire Silica 5 μm 150×30.0 mm; mobile phase, gradient from 0%NH₄OH, 100% DCMto 0.5% NH₄OH, 95% DCM, 5% MeOH). The fractions werecollected and the solvent was evaporated. The residue was furtherpurified by chiral super critical fluid chromatography (CHIRALPAK AD-H 5μm 250×20 mm; mobile phase, 0.3% 2-propylamine, 40% EtOH, 60% CO₂). Theproduct fractions were collected and the solvent was evaporated. Theresidue (0.220 g, 38%) was dissolved from CH₃CN and cooled at 5° C. Asolution of HCl 5N/iPrOH (0.258 mL) was added dropwise at 5° C. and themixture was evaporated till dryness. The residue was triturated fromdiethyl ether, filtered and dried under vacuum at 60° C., yielding 0.215g (32%) of compound 105.

Conversion 36 Preparation of Compound 109

Sodium azide (84.1 mg, 1.29 mmol) was added at 5° C. to a solution offormaldehyde (0.65 mL, 8.62 mmol) and HOAc (74p1, 1.29 mmol) in dioxane(1.5 mL). The reaction mixture was stirred for 15 minutes and a solutionof compound 38 (310 mg, 0.78 mmol) in dioxane (1.5 mL) was added. Thereaction mixture was stirred at 5° C. for 10 minutes, then sodiumL-ascorbate (34 mg, 0.17 mmol) was added, followed by a solution ofcopper sulfate in water (0.53 mL, 0.043 mmol). The reaction mixture wasallowed to warm to room temperature and stirred for 3 hours. Water wasadded and the reaction mixture was extracted with EtOAc. The organiclayer was decanted, washed with brine, dried (MgSO₄), filtered andevaporated to dryness, yielding 367 mg (100%) of compound 109.

Conversion 37 Preparation of Compound 110

To a solution of compound III (prepared according to conversion 5areaction from compound 129) (170 mg, 0.29 mmol) in DCM (20 mL) was added1-chloroethyl chloroformate (37p1, 0.34 mmol) and the reaction wasstirred at room temperature for 90 minutes. The solvent was removedunder reduced pressure. To the residue was added MeOH (20 mL) and thesolution was heated to 40° C. for 1 hour. The reaction mixture wascooled to room temperature and evaporated under reduced pressure toyield a red solid. The residue (170 mg) was purified by chromatographyover silica gel (Hyperprep C18 HS BDS100A 8 mu (Shandon); mobile phase,gradient from 80% of a 0.5% solution of ammonium carbonate in water, 20%MeOH to 20% of a 0.5% solution of ammonium carbonate in water, 80%MeOH). The product fractions were collected and the solvent wasevaporated, yielding 64 mg (44%) of compound 110.

Conversion 38 Preparation of Compound 82

Dess-martin periodinane (5.16 mL, 1.55 mmol) was added dropwise at 0° C.to compound 113 (0.59 g, 1.41 mmol) in DCM (10 mL) under N₂ flow. Themixture was stirred at room temperature for 2 hours, poured out into iceand basified with an aqueous solution of K₂CO₃ (10%). The organic layerwas extracted with DCM, dried (MgSO₄), filtered off and evaporated tilldryness. The residue was purified by chromatography over silica gel(Irregular SiOH, 15-40 μm; mobile phase, gradient from 98% DCM/2% MeOHto 95% DCM/5% MeOH). The pure fractions were collected and the solventwas evaporated yielding 0.47 g (65%) of compound 82.

Conversion 39 Preparation of Compound 114

Sodium hydride (104 mg; 2.61 mmol) was added portionwise to a solutionof compound 115 (500 mg; 0.87 mmol) in N,N-dimethylformamide (8 mL) at5° C. under N₂ flow. The reaction mixture was stirred at 5° C. for 1hour, then a solution of iodomethane (0.16 mL; 2.61 mmol) was addeddropwise at 5° C. The reaction mixture was stirred overnight at roomtemperature. The reaction was poured out into ice water and EtOAc wasadded. The organic layer was separated, washed with brine, dried(MgSO₄), filtered and the solvent was evaporated. The obtained residue(0.55 g) was purified by chromatography over silica gel (Irregular SiOH,15/40 μm, 30 g; mobile phase, gradient from 100% DCM to 96% DCM, 4%MeOH. The product fractions were collected and the solvent wasevaporated, yielding 0.39 g (76%) of compound 114.

Conversion 40 Preparation of Compound 116

Sodium hydride (0.066 g, 1.66 mmol) was added portionwise to a solutionof compound 117 (0.51 g, 0.83 mmol) in N,N-dimethylformamide (10 mL) at5° C. under N₂ flow. The mixture was stirred for 1 hour at 5° C., theniodomethane (0.103 mL, 1.66 mmol) was added portionwise at 5° C. Thereaction mixture was stirred for 1 hour at 5° C., then warmed to roomtemperature. The mixture was stirred at room temperature overnight. Themixture was poured out into ice water and EtOAc was added. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue was purified by chromatography over silica gel(Irregular SiOH, 15/40 μm, 30 g MERCK; mobile phase, gradient from 100%DCM to 98% DCM, 2% MeOH). The product fractions were collected and thesolvent was evaporated, yielding 0.400 g (76%) of compound 116.

Conversion 41 a) Preparation of Compound 118

To a stirred mixture of ethylenediamine (0.226 mL, 3.38 mmol) and drytoluene (15 mL) cooled on an ice bath and under nitrogen was addeddropwise trimethylaluminium in heptane (1M, 4 mL, 4 mmol). The mixturewas stirred at room temperature for 60 minutes and then compound 65 (300mg, 0.670 mmol) in dry toluene (7 mL) was added. The mixture was heatedto reflux for 3 hours and was then allowed to cool to room temperature.MeOH (50 mL) was added cautiously. The mixture was stirred at roomtemperature for 5 minutes and then filtered through Celite. The organiclayers were concentrated and purified over chromatography over silicagel. The desired fractions were collected and the solvent evaporated,yielding compound 118((4,5-dihydro-1H-imidazol-2-ylmethyl)-(3,5-dimethoxy-phenyl)-[3-(1-methyl-1H-pyrazol-4-yl)-quinoxalin-6-yl]-amine) (100 mg).

b) Preparation of Compound 119

Compound 118 was heated to 100° C. in aqueous sodium hydroxide (2N, 5mL) overnight to promote the ring opening reaction. 1,4-dioxane wasadded (5 mL) and the reaction was continued for a further 10 hours at100° C. The reaction was allowed to cool and was extracted with EtOAc(2×). The organic layers were dried (MgSO₄) and concentrated.Hydrochloric acid in MeOH was added and the product was precipitatedwith diethyl ether. The bright red solid was isolated by filtration andwas dried in a vacuum oven to give compound 119(N-(2-Amino-ethyl)-2-{(3,5-dimethoxy-phenyl)-[3-(1-methyl-1H-pyrazol-4-yl)-quinoxalin-6-yl]-amino}-acetamide)(80 mg).

Conversion 42 Preparation of Compound 120

To a solution of compound 84 (36 mg, 0.89 mol, 1 equiv.) in dioxane (3mL) and DMF (1.5 mL) was added 1-iodo-2-fluoroethane (16 mg, 0.89 mmol)and K₂CO₃ (25 mg, 1.78 mmol). The reaction mixture was heated to 90° C.for 5.5 hours and a further amount of DMF was added (1.5 mL) and thereaction mixture was heated to 100° C. for 1.5 hour. The solvents wereremoved under reduced pressure and the reaction mixture was partitionedbetween EtOAc and water. The layers were separated, dried (MgSO₄) andconcentrated under reduced pressure. The crude mixture was purified byHPLC to give compound 120 (17 mg).

Conversion 43 Preparation of Compound 124

A solution of compound 76 (0.254 g; 0.608 mmol), potassium phtalimide(0.68 g, 3.65 mmol) in N-methyl-pyrrolidone (5 mL) was heated undermicrowave irradiation for 1.5 hour at 150° C. The solution was cooledand the mixture was poured into cooled water. The product was extractedwith EtOAc. The organic layer was washed with H₂O, dried (MgSO₄),filtered and evaporated to dryness to give compound 124 used withoutfurther purification for the next step.

Conversion 44 Preparation of Compound 125

Compound 124 was heated in EtOH (20 mL) with hydrazine monohydrate (0.57mL; 18.25 mmol) at 80° C. for 5 hours. The mixture was cooled to roomtemperature, evaporated and the residue was poured into water. Theorganic layer was extracted with DCM, washed with brine, dried (MgSO₄),filtered and evaporated to dryness to give 400 mg of crude product. Theresidue was purified by chromatography over silica gel (Spherical SiOH,10 μm, 60 g, PharmPrep MERCK; mobile phase 0.5% NH₄OH, 95% DCM, 5%MeOH). The pure fractions were collected and evaporated to give 140 mg(53%) of compound 125. MP=99° C. (DSC).

Conversion 45 Preparation of Compound 606

A solution of compound 605 (5.3 g; 11.55 mmol) in THF dry (105 mL) wasadded dropwise to a solution of lithium aluminium hydride (0.789 g;20.79 mmol) in THF dry (105 mL) at 0° C. under a N₂ flow. The reactionmixture was stirred for 2 hours at 0° C. EtOAc was added dropwise to thereaction mixture, then water was added dropwise. The organic layer wasseparated, washed with brine, dried (MgSO₄), filtered and the solventwas evaporated to dryness. The residue (5 g) was purified bychromatography over silica gel (Irregular SiOH, 20-45 μm, 1000 g; mobilephase gradient from 0.1% NH₄OH, 97% DCM, 3% MeOH to 0.1% NH₄OH, 94% DCM,6% MeOH). The pure fractions were collected and concentrated. Theresidue (4 g, 75%) was crystallized from DIPE. The precipitate wasfiltered off and dried under vacuum, yielding 3.5 g (65%) of thecompound 606. MP: 97° C. (DSC)

Conversion 46 Preparation of Compounds 608, 609, 610, 611

*means relative stereochemistry

Compound 607 (7.4 g; 6.74 mmol), hydrazine monohydrate (2.52 mL; 80.94mmol) in EtOH (240 mL) was heated at 80° C. for 2 hours. The reactionmixture was cooled to room temperature and poured out into ice water.DCM was added and the organic layer was separated, washed with water,dried (MgSO₄), filtered and the solvent was evaporated until dryness.The residue (5.1 g) was purified by chromatography over silica gel(Irregular; SiOH 20-45 μm; 450 g; mobile phase 0.5% NH₄OH, 93% DCM, 7%MeOH). The product fractions were collected and the solvent wasevaporated to give 1.1 g of fraction I=compound 896 (enantiomericmixture) and 1.1 g of fraction II=compound 897 (enantiomeric mixture).

The enantiomers of fraction I and II were separated by chiral supercritical fluid chromatography (CHIRALPAK AD-H 5 μm 250×20 mm; mobilephase, 0.3% 2-propylamine, 60% CO₂, 40% isopropanol). The desiredproduct fractions were collected and the solvent was evaporated. Thefirst eluted enantiomer of fraction I (0.52 g) was crystallized inCH₃CN, yielding 0.325 g (12%) of compound 608 (R*, MP=159° C. (DSC)).The second enantiomer of fraction I (0.53 g) was crystallized in CH₃CN,yielding 0.284 g (10%) of compound 609 (S*, MP=155° C. (DSC)).

The first eluted enantiomer of fraction II (0.47 g) was crystallized inCH₃CN/diethyl ether, yielding 0.327 g (12%) of compound 610 (R*, MP=150°C. (DSC)). The second enantiomer of fraction II (0.475 g) wascrystallized in CH₃CN, yielding 0.258 g (9%) of compound 611 (S*,MP=148° C. (DSC)).

Conversion 47 a) Preparation of Compound 612

Boron tribromide (11.55 mL; 11.55 mmol) was added dropwise to a solutionof compound 202 in DCM (10 mL) at 0° C. The solution was allowed to riseslowly to room temperature and stirred for 3 days. The reaction wasquenched with MeOH at 0° C. Then, a solution of saturated NH₃ was addedto neutralize the reaction mixture. The reaction was poured out into icewater and EtOAc was added. The organic layer was separated, washed withbrine, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (1 g) was purified by chromatography over silica gel (C18, 10μm, 250 g, 5 cm; mobile phase 0.25% (NH₄)₂CO₃ solution in water, CH₃CN).The pure fractions were collected and concentrated to afford 0.160 g(22%) of compound 612.

b) Preparation of Compound 613

Potassium carbonate (0.057 g; 0.41 mmol) was added to a solution ofcompound 612(0.080 g; 0.21 mmol) in N,N-dimethylformamide (15 mL). Thereaction mixture was stirred at room temperature for 1 hour. Then methyliodine (0.013 mL; 0.21 mmol) was added to the reaction mixture andstirred at room temperature for 4 days. The reaction mixture wasconcentrated under reduced pressure to approximatelyl/3 of its initialvolume. The residue was poured out into ice water and EtOAc was added.The organic layer was separated, washed with brine, dried (MgSO₄),filtered and the solvent was evaporated. The residue (0.05 g) waspurified by chromatography over silica gel (RP Vydac Denali C18, 10 μm,250 g, 5 cm; mobile phase 0.25% (NH₄)₂CO₃ solution in water, CH₃CN). Thepure fractions were collected and concentrated. The residue (0.025 g)was separated by chiral super critical fluid chromatography (CHIRALPAKDiacel OJ-H 20×25 0 mm; mobile phase, CO₂, MeOH with 0.2%2-propylamine). The desired product fractions were collected and thesolvent was evaporated to give 0.007 g (9%) of compound 613.

Conversion 48 Preparation of Compound 625

Iodomethane (0.096 mL; 1.54 mmol) was added to a solution of compound624 (0.73 g; 1.54 mmol) and K₂CO₃ (0.213 g; 1.54 mmol) in CH₃CN (20 mL).The reaction mixture was stirred at 60° C. for 5 hours. The reactionmixture was poured out into ice water and EtOAc was added. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (0.666 g) was purified by chromatography oversilica gel (Spherical SiOH, 10 μm, 60 g; mobile phase gradient from 0.5%NH₄OH, 95% DCM, 5% MeOH to 1% NH₄OH, 90% DCM, 10% MeOH). The purefractions were collected and concentrated to give 0.3 g (38%) ofcompound 625. MP: 156° C. (DSC).

Conversion 49 a) Preparation of Compound 626

Compound 38 (2 g; 5.0 mmol) was dissolved in THF (80 mL), then thesolution was cooled at −78° C. and n-butyllithium 1.6M in hexane (3.1mL; 5.0 mmol) was added. The reaction mixture was allowed to slowly riseto −30° C. and stirred for 45 minutes. 1-Boc-azetidinone (0.715 g; 4.17mmol) in THF (8 mL) was added to the reaction mixture at −78° C. andstirred for 1 hour, then the reaction mixture was allowed to rise toroom temperature for 1 hour. The solution was poured out into ice waterand NH₄Cl, EtOAc were added. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue (2.86 g)was purified by chromatography over silica gel (Irregular SiOH, 20-45μm, 450 g; mobile phase 0.1% NH₄OH, 96% DCM, 4% MeOH). The purefractions were collected and concentrated to give 0.343 g (15%) ofcompound 626.

b) Preparation of Compound 627

Trifluoroacetic acid (1.4 mL; 17.9 mmol) was added to a solution ofcompound 626 (0.17 g; 0.3 mmol). The reaction was stirred at 70° C. for2 hours. The reaction mixture was cooled to room temperature andevaporated. The reaction mixture was poured out into ice water, DCM wasadded and basified with NH₄OH. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue (0.35 g)was purified by chromatography over silica gel (Irregular SiOH, 15-40μm, 30 g; mobile phase 0.5% NH₄OH, 95% DCM, 5% MeOH). The pure fractionswere collected and concentrated to give 0.048 g (34%) of compound 627.

Conversion 50 Preparation of Compounds 628 and 629

NaH (0.22 g; 5.56 mmol) was added portionwise to compound 14 (0.5 g; 1.1mmol) in THF (30 mL). The reaction mixture was stirred at 0° C. for 1hour. Then, acetyl chloride (0.8 mL; 11.1 mmol) was added dropwise at 5°C. under N₂ flow. The reaction mixture was stirred at 50° C. for 18hours. The reaction was poured out into ice water and EtOAc was added.The organic layer was separated and washed with brine, dried (MgSO₄),filtered and the solvent was evaporated. The residue (0.51 g) waspurified by chromatography over silica gel (SiOH 5 μm, 250*30 mm; mobilephase gradient from 100% DCM to 0.5% NH₄OH, 95% DCM, 5% MeOH). The purefractions were collected and concentrated to give 220 mg of product. Theenantiomers were separated by chiral super critical fluid chromatography(CHIRALPAK AD-H 5 μm 250×20 mm; mobile phase, 60% CO₂, 40% isopropanol).The desired product fractions were collected and the solvent wasevaporated. The first eluted enantiomer (0.105 g) was crystallized indiethyl ether, yielding 0.050 g (9%) of compound 628 (S*, MP=122° C.).The second enantiomer (0.096 g) was crystallized in diethyl ether,yielding 0.051 g (9%) of compound 629 (R*, MP=124° C.).

Conversion 51 Preparation of Compound 631

as a HCl Salt

Trifluoroacetic acid (0.52 mL; 6.9 mmol) was added to a solution ofcompound 630 (0.4 g; 0.7 mmol) in DCM (7 mL). The reaction was stirredat room temperature for 24 hours. The reaction mixture was poured outinto ice water, DCM was added and basified with K₂CO₃. The organic layerwas separated, dried (MgSO₄), filtered and the solvent was evaporated.The residue (0.5 g) was purified by chromatography over silica gel(Irregular SiOH, 15-40 μm, 30 g; mobile phase 0.5% NH₄OH, 97% DCM, 3%MeOH). The pure fractions were collected and concentrated. HCl inisopropyl alcohol 5N was added dropwise to the residue (0.41 g). Acetoneand diethyl ether were added. The precipitate was filtered off and driedin vacuum to give 0.383 g (98%) of compound 631. MP: 189° C. (Kofler)

Conversion 52 Preparation of Compound 633

1,1′ carbonyldiimidazole (1.1 g, 6.6 mmol) was added portion wise to asolution of compound 297 (2.4 g; 5.6 mmol) in DCM (60 mL). Then therecation mixture was stirred at room temperature for 1 hour.N,O-dimethylhydroxylamine hydrochloride (0.65 g; 6.6 mmol) was added andthe reaction mixture was stirred at room temperature for 72 hours. Thereaction mixture was quenched with water and extracted with DCM. Theorganic layer was decanted, dried (MgSO₄), filtered and evaporated todryness. The residue (2.6 g) was purified by chromatography over silicagel (Irregular SiOH 15-40 μm, 300 g; mobile phase 0.3% NH₄OH, 98% DCM,2% MeOH). The pure fractions were collected and concentrated to give0.185 g (11%). The residue (0.5 g) was crystallized from diethyl ether.The precipitate was filtered and dried to afford 0.28 g (11%) ofcompound 633. MP: 130° C. (DSC)

Conversion 53 Preparation of Compound 635

Compound 634 (0.26 g; 0.53 mmol) was hydrogenated at room temperature inEtOAc (10 mL) with Pd/C (0.05 g) as a catalyst under atmosphericpressure. After 18 hours the catalyst was filtered off on a pad ofCelite® and the filtrate was concentrated in vacuo until dryness. Theresidue (0.256 g) was purified by chromatography over silica gel(SiOHSiOH, 5 μm, 150*30 mm; mobile phase gradient from 100% DCM to 0.8%NH₄OH, 92% DCM, 8% MeOH). The pure fractions were collected andconcentrated. The residue (0.085 g) was crystallized from CH₃CN/DIPE.The precipitate was filtered and dried to afford 0.075 g (29%) ofcompound 635. MP: 110° C. (DSC)

Conversion 54 Preparation of Compounds 637 and 636

Compound 634 (0.38 g; 0.78 mmol) was hydrogenated at room temperature inEtOAc (40 mL) with Lindlar catalyst (0.075 g) as a catalyst underatmospheric pressure. After 9 hours the catalyst was filtered off on apad of Celite®, washed with DCM/MeOH and the filtrate was concentratedin vacuo until dryness. The residue (0.474 g) was purified bychromatography over silica gel (SiOHSiOH, 5 μm, 150*30 mm; mobile phasegradient from 100% DCM to 0.8% NH₄OH, 92% DCM, 8% MeOH). The purefractions were collected and concentrated to give two fractions. Thefirst fraction (0.135 g) was crystallized from diethyl ether. Theprecipitate was filtered and dried to afford 0.099 g (26%) of compound636 (Z). MP: >260° C. (Kofler). The second fraction was crystallizedfrom diethyl ether. The precipitate was filtered and dried to afford0.048 g (13%) of compound 637 (E). MP: 80° C. (Kofler).

Conversion 55 Preparation of Compound 640

Potassium tert-butoxide (0.054 g; 0.48 mmol) was added to a solution ofcompound 809 (0.24 g; 0.48 mmol) in THF (15 mL) and the reaction mixturewas stirred at 10° C. for 2 hours. The reaction was poured out into icewater and EtOAc was added. The organic layer was separated and washedwith brine, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (0.44 g) was purified by chromatography over silica gel (SiOH 5μm, 150*30 mm; mobile phase gradient from 70% Heptane, 2% MeOH, 28%EtOAc to 20% MeOH, 80% EtOAc). The pure fractions were collected andconcentrated. The residue (0.132 g) was crystallized from diethyl ether.The precipitate was filtered and dried to afford 0.087 g (37%) ofcompound 640. MP: 241° C. (DSC).

Conversion 56 Preparation of Compound 642

A mixture of compound 137 (0.51 g; 1.1 mmol), 3-bromopropionitrile (0.11mL; 1.4 mmol) and K₂CO₃ (0.8 g; 5.6 mmol) in CH₃CN (15 mL) was stirredat 80° C. for 6 hours. The reaction was poured out into ice water andEtOAc was added. The organic layer was separated and washed with brine,dried (MgSO₄), filtered and the solvent was evaporated. The residue (0.5g) was purified by chromatography over silica gel (SiOH 5 μm, 150*30 mm;mobile phase gradient from 0.2% NH₄OH, 98% DCM, 2% MeOH to 0.9% NH₄OH,91% DCM, 9% MeOH). The pure fractions were collected and concentrated.The residue (0.35 g) was crystallized from diethyl ether. Theprecipitate was filtered and dried to afford 0.257 g (47%) of compound642. MP: 127° C. (DSC).

Conversion 57 Preparation of Compound 643

as a HCl Salt

3-hydroxytetrahydrofuran (0.19 mL; 2.3 mmol) and triphenylphosphine(0.61; 2.3 mmol) was added to a solution of compound 137 (0.5 g; 1.16mmol) in THF (14 mL) under N₂ flow. The reaction mixture was stirred atroom temperature for 10 minutes, then diisopropyl azodicarboxylate (0.46mL; 2.3 mmol) was added and the reaction mixture was stirred for 24hours. The reaction was poured out into ice water and EtOAc was added.The organic layer was separated and washed with brine, dried (MgSO₄),filtered and the solvent was evaporated. The residue (2 g) was purifiedby chromatography over silica gel (SiOH5 μm, 150*30 mm; mobile phase0.5% NH₄OH, 95% DCM, 5% MeOH). The pure fractions were collected andconcentrated. The residue (0.19 g) was dissolved in MeOH, 2.3 mL of HCli-PrOH was added, then the chlorhydrate was crystallized from diethylether. The precipitate was filtered off and dried to afford 0.178 g(25%) of compound 643.MP: 160° C. (Kofler)

Conversion 58 Preparation of Compound 648

A mixture of compound 297 (1.65 g, 3.8 mmol), 2,2,2-trifluoroethylamine(1.4 mL, 9.4 mmol), 1-hydroxybenzotriazole (3.6 g, 9.4 mmol),triethylamine (1 mL, 7.5 mmol) in N,N-dimethylformamide (50 mL) wasstirred at room temperature for 18 hours. The reaction mixture waspoured out into ice water and EtOAc was added. The organic layer wasseparated, washed with brine, dried (MgSO₄), filtered and the solventwas evaporated. The residue (3.2 g) was purified by chromatography oversilica gel (Irregular Silica 20×40; mobile phase 0.1% NH₄OH, 97% DCM, 3%MeOH). The product fraction was collected and the solvent wasevaporated. The residue was triturated from diethyl ether, filtered anddried under vacuum at 60° C., yielding 1.15 g (65%) of compound 648,MP=196° C. (DSC).

Conversion 59 Preparation of Compound 651

Trifluoroacetic acid (1 mL; 14.3 mmol) was added to a solution ofcompound 650 (0.44 g; 0.7 mmol) in DCM (5.2 mL) at 0-5° C. The reactionmixture was stirred at room temperature for 2 hours, then was quenchedwith K₂CO₃ 10%. The organic layer was washed with water, dried (MgSO₄),filtered and evaporated till dryness. The residue (0.45 g) was purifiedby chromatography over silica gel (Irregular Silica 15×40; 30 g, mobilephase 1% NH₄OH, 90% DCM, 10% MeOH). The product fraction was collectedand the solvent was evaporated. The residue was crystallized fromdiethyl ether/CH₃CN, filtered and dried under vacuum at 60° C., yielding0.26 g (72%) of compound 651, MP=122° C. (Kofler).

Conversion 60 Preparation of Compound 652

A suspension of compound 38 (1 g; 3.5 mmol), 2-bromo-3-methoxypyridine(0.25 g; 0.35 mmol) and Et₃N (3.0 mL; 21.5 mmol) in DMSO (20 mL) wasdegassed under N₂ flow. Dichlorobis(triphenylphosphine)-palladium (0.25g; 0.36 mmol) and copper(I) iodide (0.034 g; 0.18 mmol) were added andthe reaction mixture was stirred at 90° C. for 40 minutes. The reactionmixture was cooled to room temperature, poured out into water and EtOAcwas added. The mixture was filtered off on a pad of Celite®. The organiclayer was decanted, washed with brine, dried (MgSO₄), filtered andevaporated to dryness. The residue (1.4 g) was purified bychromatography over silica gel (Irregular SiOH, 20-40 μm, 450 g; mobilephase, 0.1% NH₄OH, 97% DCM, 3% MeOH). The pure fractions were collectedand evaporated to dryness. The residue was crystallized from diethylether. The precipitate was filtered and dried to give 0.6 g (65%) ofcompound 652. MP: 144° C. (DSC)

Conversion 61 Preparation of Compounds 656 and 657

as a HCl Salt as a HCl Salt

Compound 14a (3.4 g) was purified by chromatography over silica gel(Irregular SiOH, 15-40 μm, 300 g; mobile phase, 0.1% NH₄OH, 98% DCM, 2%MeOH). The pure fractions were collected and evaporated to dryness. Theresidue (1 g) was separated by chiral super critical fluidchromatography (CHIRALPAK AD-H 5 μm 250×20 mm; mobile phase, 40%2-propylamine, 60% CO₂). The desired product fractions were collectedand the solvent was evaporated. The first eluted enantiomer (0.5 g) wasdissolved in diethyl ether, 5 equivalents of HCl in i-PrOH were addedand stirred at room temperature for 18 hours. The precipitate wasfiltered and dried to afford 0.29 g (8%) of compound 656(R*, MP=95° C.(Kofler)). The second enantiomer (0.55 g) was purified by achiral SFC on(Amino 6 μm 150*21.2 mm, mobile phase, 90% CO₂, 10% MeOH). The desiredproduct fractions were collected and the solvent was evaporated. Theresidue (0.47 g) was dissolved in diethyl ether, 5 equivalents of HCl ini-PrOH were added and stirred at room temperature for 18 hours. Theprecipitate was filtered and dried to afford 0.36 g (11%) of compound657 (S*, MP=110° C. (Kofler)).

Conversion 62 Preparation of Compound 663

Compound 662 (0.25 g; 0.49 mmol) in HCl (1M in H₂O) (12.2 mL; 12.2 mmol)was stirred at 60° C. for 24 hours. The reaction mixture was cooled downto room temperature, evaporated till dryness. Then the residue was takenup DCM and washed with K₂CO₃ 10%. The organic layer was separted anddried (MgSO₄), filtered and the solvent was evaporated. The residue (0.2g) was purified by chromatography over silica gel (SiOH 5 μm, 150*30 mm,mobile phase, gradient from 0.2% NH₄OH, 98% DCM, 2% MeOH to 1.1% NH₄OH,89% DCM, 11% MeOH). The pure fractions were collected and evaporated.The residue was crystallized from diethyl ether. The precipitate wasfiltered and dried to afford 0.1 g (41%) of compound 663. MP: 200° C.(DSC).

Conversion 63 Preparation of Compound 670

1,1′carbonyldiimidazole (0.5 g, 3 mmol) was added to a solution ofcompound 125 (1.2 g, 2.8 mmol) in THF (20.5 mL) at 0° C. under N₂ flow.The reaction mixture was stirred at room temperature for 2 hours. Thereaction was poured out into ice water and EtOAc was added. The organiclayer was washed with brine, dried (MgSO₄), filtered and evaporated. Theresidue (1.3 g) was purified by chromatography over silica gel(Irregular SiOH, 20-45 μm, 300 g; mobile phase 0.2% NH₄OH, 96% DCM, 4%iPrOH). The pure fractions were collected, the solvent was evaporated.The residue (0.98 g) was crystallized from CH₃CN and diethyl ether. Theprecipitate was filtered off and dried to give 0.8 g (64%) of compound670.MP: 157° C. (DSC).

Conversion 64 Preparation of Compound 671 and 672

A mixture of compound 76 (1.5 g; 3.6 mmol) and3-methyl-1H-1,2,4-triazole (3.7 mL; 28.9 mmol) in1-methyl-2-pyrrolidinone (4 mL) in a sealed tube was heated at 140° C.using one single mode microwave (Biotage Initiator EXP 60) for 40minutes. The reaction mixture was poured out into ice water and EtOAcwas added. The organic layer was separated, washed with brine, dried(MgSO₄), filtered and the solvent was evaporated to dryness. The crudeproduct (2.1 g) was purified by chromatography over silica gel (15-40 μm300 g; mobile phase, 0.5% NH₄OH, 93% DCM, 7% MeOH). The pure fractionswere collected and the solvent was evaporated till dryness. The residue(1 g) was purified by chromatography over silica gel (Cyano 6 μm 150*21mm; mobile phase, 90% CO₂, 10% EtOH). The desired product fractions werecollected and the solvent was evaporated. The first isomer (0.3 g) wascrystallized in CH₃CN/diethyl ether, yielding 0.26 g (15%) of compound671MP=144° C. (DSC). The second isomer (0.34 g) was crystallized inCH₃CN/diethyl ether, yielding 0.26 g (15%) of compound 672 MP=194° C.(DSC).

Conversion 65 Preparation of Compound 673

A mixture of compound 584 (0.64 g; 1.2 mmol) and methylamine in 2M THF(3 mL; 6 mmol) in 1-methyl-2-pyrrolidinone (5 mL) was heated at 140° C.for 24 hours in a sealed tube. The reaction mixture was poured out intoice water and EtOAc was added. The organic layer was separated, washedwith brine, dried (MgSO₄), filtered and the solvent was evaporated todryness. The crude product (1 g) was purified by chromatography oversilica gel (5 μm; mobile phase gradient from 100% DCM to 0.6% NH₄OH, 94%DCM, 6% MeOH). The pure fractions were collected and the solvent wasevaporated till dryness. The residue was crystallized from acetone anddiethyl ether. The precipitate was filtered and dried to give 0.34 g(58%) of compound 673. MP: 180° C. (Kofler)

Conversion 66 a) Preparation of Compound 674

Chloroacetyl chloride (0.23 mL; 2.9 mmol) was_was added dropwise to asolution of compound 409 (1.3 g, 2.7 mmol) and triethylamine (1.14 ml,8.2 mmol) in acetonitrile (40 ml) at 0° C. under nitrogen. The reactionmixture was stirred for 2 hours at room temperature, then at 110° C.overnight. Water was added and the reaction mixture was extracted withDCM, dried (MgSO₄), filtered and dried to provide 1.5 g of compound 674used without further purification in the next step.

b) Preparation of Compound 675

Potassium tert butoxide was added portionwise to a solution of compound674 (2.6 g; 4.7 mmol) in isopropanol (58 mL) and THF (58 mL). Thereaction mixture was stirred at room temperature for 2 hours, then waspoured out into ice water and DCM was added. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated todryness. The crude product (2.1 g) was purified by chromatography oversilica gel (20-45 μm 450 g; mobile phase gradient from 0.2% NH₄OH, 96.5%DCM, 3.5% MeOH to 1% NH₄OH, 89% DCM, 10% MeOH). The pure fractions werecollected and the solvent was evaporated till dryness. The residue (0.61g) was crystallized from diethyl ether and CH₃CN. The precipitate wasfiltered and dried to give 0.49 g (21%) of compound 675.MP: 187° C.(Kofler)

c) Preparation of Compound 676

Lithium aluminium hydride (0.028 g; 0.73 mmol) was added to a solutionof compound 674 (0.25 g; 0.48 mmol) in THF (20 mL) under N₂ flow between0-5° C. The reaction mixture was stirred between 0-5° C. for 1 hour.EtOAc was added dropwise to the reaction mixture, then water was addeddropwise. The organic layer was separated, washed with brine, dried(MgSO₄), filtered and the solvent was evaporated to dryness. The crudeproduct (1 g) was purified by chromatography over silica gel (5 μm;mobile phase, gradient from 100% DCM to 0.6% NH₄OH, 94% DCM, 6% MeOH).The pure fractions were collected and the solvent was evaporated tilldryness. The residue (0.155 g) was purified by achiral Super criticalfluid chromatography (2-ethylpyridine 6 μm; mobile phase 0.3%isopropylamine, 20% MeOH, 80% CO₂). The pure fractions were collectedand the solvent was evaporated till dryness.

The residue (0.053 g) was purified by chromatography over silica gel(15-40 μm 10 g; mobile phase gradient from 100% DCM to 0.6% NH₄OH, 94%DCM, 6% MeOH). The pure fractions were collected and the solvent wasevaporated till dryness to afford 0.043 g (18%) of compound 677 MP: 88°C. (Kofler)

Conversion 67 a) Preparation of Compound 678

The experiment has been performed 3 times on the following amount.

A mixture of compound 137 (HCl salt) (1 g; 2.3 mmol),2-bromoethyl-methylsulfone (0.5 mL; 2.8 mmol) and K₂CO₃ (0.6 g; 4.6mmol) in CH₃CN (33 mL) was stirred at 80° C. for 2 hours. The reactionwas poured out into ice water and EtOAc was added. The organic layerswere separated and washed with brine, combined, dried (MgSO₄), filteredand the solvent was evaporated. The residue (5.2 g) was purified bychromatography over silica gel (SiOH 15-40 μm, 450; mobile phasegradient from 0.5% NH₄OH, 96% DCM, 4% MeOH to 0.5% NH₄OH, 90% DCM, 10%MeOH). The pure fractions were collected and concentrated. The residue(3.2 g) was crystallized from diethyl ether. The precipitate wasfiltered and dried to afford 2.2 g (78%) of compound 678. MP: 148° C.(DSC).

Conversion 68 a) Preparation of Compound 680

Compound 681 (0.97 g; 1.4 mmol) in trifluoroacetic acid (28.5 mL) washeated at 100° C. for 24 hours in a sealed tube. The reaction mixturewas evaporated till dryness. The crude product was diluted in DCM andbasified with NaHCO₃. The organic layer was separated and dried (MgSO₄),filtered and the solvent was evaporated. The residue (1.2 g) waspurified by chromatography over silica gel (SiOH 15-40 μm, 300 g; mobilephase gradient from 0.5% NH₄OH, 92% DCM, 8% MeOH to 0.5% NH₄OH, 90% DCM,10% MeOH). The pure fractions were collected and concentrated. Theresidue (0.4 g) was purified by chromatography over silica gel (SiOH 10μm, 60 g; mobile phase 0.5% NH₄OH, 93% DCM, 7% MeOH). The pure fractionswere collected and concentrated. The residue was crystallized fromDIPE/CH₃CN. The precipitate was filtered and dried to give 0.29 g (45%)of compound 680. MP: 167° C. (DSC).

Conversion 69 a) Preparation of Compound 682

Palladium 10% on carbon (0.65 g; 6 mmol) was added to a solution ofcompound 10 (1.5 g; 2.7 mmol) in MeOH (30 mL). The reaction mixture wasstirred at room temperature under 3 bars. After 24 hours the catalystwas filtered off on a pad of Celite® and the filtrate was concentrated.The residue (1.2 g) was purified by chromatography over silica gel (SiOH20-40 μm, 450 g; mobile phase gradient from 0.2% NH₄OH, 96% DCM, 4% MeOHto 0.2% NH₄OH, 95% DCM, 5% MeOH). The pure fractions were collected andconcentrated. The residue (0.25 g) was purified by achiral supercritical fluid chromatography (2-ethylpyridine 6 μm; mobile phase 0.3%isopropylamine, 20% MeOH, 80% CO₂). The pure fractions were collectedand the solvent was evaporated till dryness. The residue wascrystallized from diethyl ether and CH₃CN. The precipitate was filteredoff and dried to afford 0.15 g (12%) of compound 682.MP: 149° C.(Kofler).

Conversion 70 a) Preparation of Compound 683

A mixture of compound 84 (1 g; 2.5 mmol) and1.2-epoxy-3.3.3-trifluoropropane (0.4 mL; 4.9 mmol) in MeOH (15 mL) washeated at 60° C. for 2 hours. The reaction mixture was cooled down toroom temperature and evaporated till dryness. The residue (1.6 g) waspurified by chromatography over silica gel (SiOH, 15-40 μm, 300 g;mobile phase gradient from, 0.1% NH₄OH, 98% DCM, 2% MeOH to 0.1% NH₄OH,97% DCM, 3% MeOH). The pure fractions were collected and concentrated.The residue (0.56 g) was crystallized from diethyl ether. Theprecipitate was filtered and dried to afford 0.2 g (16%) of compound683. MP: 123° C. (DSC).

Conversion 71 Preparation of Compound 685

as a HCl Salt

At 5° C., A 5N solution of HCl in i-PrOH 5/6N (2.4 mL; 12 mmol) wasadded to a solution of compound 686 (0.9 g; 1.7 mmol) in CH₃OH (3 mL).The reaction mixture was stirred at 5° C. for 2 hours, then for 15 hoursat room temperature. The precipitate was filtered off and dried undervacuum to afford 0.425 g (52%) of compound 685. MP=203° C. (Kofler).

Conversion 72 Preparation of Compound 696

as a HCl Salt

Hydrogen chloride (4M in dioxane) (6.8 mL; 27.2 mmol) was added to asolution of compound 695 (1.9 g; 3.4 mmol) in CH₃CN (37 mL) and wasstirred at 50° C. for 18 hours. The reaction mixture was poured out intoice water. The precipitate was filtered and dried to give 0.3 g (15%) ofcompound 696. MP: 188° C. (Kofler)

Conversion 73 Preparation of Compound 902

A mixture of compound 669 (200 mg, 0.38 mmol) and bromotrimethylsilane(3.16 ml, 23.975 mmol) in anhydrous DCM (4 ml) was stirred at roomtemperature for 3 hours. The solvent was evaporated, the resultingresidue was diluted with MeOH-Water (1:1, 10 ml) and stirred for 20minutes. The precipitate was filtered, washed with AcOEt and dried togive 149 mg (82%) of compound 902.

Conversion 74 Preparation of Compound 906

Compound 93 (340 mg, 0.81 mmol) was added at 0° C. totrifluoroacetaldehyde methyl hemiketal (311 μL, 3.25 mmol) and themixture was stirred at 0° C. for 4 h30. The mixture was evaporated andthe residue purified by chromatography over silica gel (5 μm. mobilephase: gradient from 0.2% NH₄OH, 98% DCM, 2% MeOH to 1.3% NH₄OH, 87%DCM, 13% MeOH). The desired product fractions were collected and thesolvent was evaporated. yielding 41 mg. The residuet was taken up inEt₂O filtered and dried. to give 29 mg of compound 906.

Conversion 75 Preparation of Compound 918

A mixture of compound 584 (397 mg; 0.75 mmol), dimethylamine (3 mL of a2.0 M solution in tetrahydrofuran; 6 mmol) in 1-methyl-2-pyrrolidinone(11 mL) was stirred at 140° C. for 24 hours in a sealed tube. Themixture was poured into ice-water and EtOAc was added. The organic layerwas separated, dried (MgSO₄), filtered and the filtrate was evaporateduntil dryness to afford 607 mg of residue, which was purified bychromatography over silica gel (15-40 μm, 90 g, mobile phaseDCM/CH₃OH/NH₄OH: 98/2/0.1) The desired fractions were collected andevaporated to dryness to give 461 mg of residue which was repurified bychromatography over silica gel (5 μm, mobile phase: gradient from 100%DCM to 0.6% NH₄OH, 94% DCM, 6% MeOH) The desired fractions werecollected and evaporated to dryness to give 390 mg. This residue waspurified by achiral Supercritical Fluid Chromatography on(Diethylaminopropyl 5 μm, mobile phase 0.3% isopropylamine, 92% CO₂, 8%MeOH). The desired fractions were collected and evaporated to dryness togive 233 mg of residue which were. crystallized from Et₂O. Theprecipitate was filtered and dried to give 211 mg (57%) of compound 918.

Conversion 76 Preparation of Compound 757

At 5° C., under N₂ atmosphere, NaH (447.83 mg, 11.2 mmol) was added to amixture of compound 4 (2 g, 4.48 mmol) in DMF (40 mL). The reactionmixture was stirred at 10° C. for 30 minutes, then iodomethane (0.335ml, 5.375 mmol) was asdded dropwise. The reaction mixture was cooled toroom temperature and stirred at room temperature for 2 hours. Pouredinto H₂O+NaCl and extracted with AcOEt. The organic layer was washedwith H₂O, dried (MgSO₄), filtered and evaporated to dryness to give 2 gof residue. The residue was purified by flash chromatography over silicagel (15-40 μm, 40 g, CH₂Cl₂/CH₃OH/NH₄OH: 96/4/0.1). The pure fractionswere collected and evaporated to dryness to give 2 fractions: 1.05 g ofcompound 757 and 0.3 g of compound 757.

The following compounds were prepared according to reaction protocols ofone of the above Examples using alternative starting materials asappropriate. Those indicated with NMR* have NMR data hereinafter.

In the table =CoX (or =BX) indicates that the preparation of thiscompound is described in Conversion X (or Method BX).

In the table ˜CoX (or ˜BX) indicates that this compound is preparedaccording to Conversion X (or Method BX).

As understood by a person skilled in the art, compounds synthesisedusing the protocols as indicated may exist as a solvate e.g. hydrate,and/or contain residual solvent or minor impurities. Compounds isolatedas a salt form, may be integer stoichiometric i.e. mono- or di-salts, orof intermediate stoichiometry.

Analytical Part LC/GC/NMR General Procedure A

The HPLC measurement was performed using an Alliance HT 2790 (Waters)system comprising a quaternary pump with degasser, an autosampler, acolumn oven (set at 40° C., unless otherwise indicated), a diode-arraydetector (DAD) and a column as specified in the respective methodsbelow. Flow from the column was split to a MS spectrometer. The MSdetector was configured with an electrospray ionization source. Massspectra were acquired by scanning from 100 to 1000 in 1 second using adwell time of 0.1 second. The capillary needle voltage was 3 kV and thesource temperature was maintained at 140° C. Nitrogen was used as thenebulizer gas. Data acquisition was performed with a Waters-MicromassMassLynx-Openlynx data system.

Method 1

In addition to the general procedure A: Reversed phase HPLC was carriedout on an Xterra MS C18 column (3.5 μm, 4.6×100 mm) with a flow rate of1.6 ml/min. Three mobile phases (mobile phase A: 95% 25 mMammoniumacetate+5% acetonitrile; mobile phase B: acetonitrile; mobilephase C: methanol) were employed to run a gradient condition from 100% Ato 1% A, 49% B and 50% C in 6.5 minutes, to 1% A and 99% B in 1 minuteand hold these conditions for 1 minute and reequilibrate with 100% A for1.5 minutes. An injection volume of 10 μl was used. Cone voltage was 10V for positive ionization mode and 20 V for negative ionization mode.

Method 2

In addition to the general procedure A: Column heater was set at 45° C.Reversed phase HPLC was carried out on an Atlantis C18 column (3.5 μm,4.6×100 mm) with a flow rate of 1.6 ml/min. Two mobile phases (mobilephase A: 70% methanol+30% H₂O; mobile phase B: 0.1% formic acid inH₂O/methanol 95/5) were employed to run a gradient condition from 100% Bto 5% B+95% A in 9 minutes and hold these conditions for 3 minutes. Aninjection volume of 10 μl was used.

Cone voltage was 10 V for positive ionization mode and 20 V for negativeionization mode.

Method 3

In addition to the general procedure A: Reversed phase HPLC was carriedout on an Xterra MS C18 column (3.5 μm, 4.6×100 mm) with a flow rate of1.6 ml/min. Three mobile phases (mobile phase A: 95% 25 mMammoniumacetate+5% acetonitrile; mobile phase B: acetonitrile; mobilephase C: methanol) were employed to run a gradient condition from 100% Ato 50% B and 50% C in 6.5 minutes, to 100% B in 1 minute, 100% B for 1minute and reequilibrate with 100% A for 1.5 minutes. An injectionvolume of 10 μl was used.

Cone voltage was 10 V for positive ionization mode and 20 V for negativeionization mode.

Method 9

In addition to the general procedure A: Reversed phase HPLC was carriedout on a Waters Xterra-RP C18 column (3.5 μm, 4.6×100 mm) with a flowrate of 0.8 ml/min. Two mobile phases (mobile phase A: 100% 7 mMammonium acetate; mobile phase B: 100% acetonitrile) were employed torun a gradient condition from 80% A and 20% B (hold for 0.5 minute) to90% B in 4.5 minutes, 90% B for 4 minutes and reequilibrated withinitial conditions for 3 minutes. An injection volume of 5 ml was used.Cone voltage was 20 V for positive and negative ionization mode. Massspectra were acquired by scanning from 100 to 1000 in 0.4 seconds usingan interscan delay of 0.3 seconds.

Method 10

In addition to the general procedure A: Reversed phase HPLC was carriedout on a Xterra-MS C18 column (3.5 μm, 4.6×100 mm) with a flow rate of0.8 ml/min. Two mobile phases (mobile phase A: 100% 7 mM ammoniumacetate; mobile phase B: 100% acetonitrile; were employed to run agradient condition from 80% A, 20% B (hold for 0.5 minute) to 10% A, 90%B in 4.5 minutes, hold at 10% A and 90% B for 4 minutes andreequilibrated with initial conditions for 3 minutes. An injectionvolume of 10 ml was used. Cone voltage was 20 V for positive andnegative ionization mode. Mass spectra were acquired by scanning from100 to 1000 in 0.4 seconds using an interscan delay of 0.3 seconds

General Procedure B

The LC measurement was performed using an Acquity UPLC (Waters) systemcomprising a binary pump, a sample organizer, a column heater (set at55° C.), a diode-array detector (DAD) and a column as specified in therespective methods below. Flow from the column was split to a MSspectrometer. The MS detector was configured with an electrosprayionization source. Mass spectra were acquired by scanning from 100 to1000 in 0.18 seconds using a dwell time of 0.02 seconds. The capillaryneedle voltage was 3.5 kV and the source temperature was maintained at140° C. Nitrogen was used as the nebulizer gas. Data acquisition wasperformed with a Waters-Micromass MassLynx-Openlynx data system.

Method 4

In addition to the general procedure B: Reversed phase UPLC (UltraPerformance Liquid Chromatography) was carried out on a bridgedethylsiloxane/silica hybrid (BEH) C18 column (1.7 μm, 2.1×50 mm; WatersAcquity) with a flow rate of 0.8 ml/min. Two mobile phases (mobile phaseA: 0.1% formic acid in H₂O/methanol 95/5; mobile phase B: methanol) wereused to run a gradient condition from 95% A and 5% B to 5% A and 95% Bin 1.3 minutes and hold for 0.2 minutes. An injection volume of 0.5 μlwas used. Cone voltage was 10 V for positive ionization mode and 20 Vfor negative ionization mode.

Method 5

In addition to the general procedure B: Reversed phase UPLC (UltraPerformance Liquid Chromatography) was carried out on a bridgedethylsiloxane/silica hybrid (BEH) C18 column (1.7 μm, 2.1×50 mm; WatersAcquity) with a flow rate of 0.8 ml/min. Two mobile phases (25 mMammonium acetate in H₂O/acetonitrile 95/5; mobile phase B: acetonitrile)were used to run a gradient condition from 95% A and 5% B to 5% A and95% B in 1.3 minutes and hold for 0.3 minutes. An injection volume of0.5 μl was used. Cone voltage was 30 V for positive ionization mode and30 V for negative ionization mode.

General Procedure C

The LC measurement was performed using a UPLC (Ultra Performance LiquidChromatography) Acquity (Waters) system comprising a binary pump withdegasser, an autosampler, a diode-array detector (DAD) and a column asspecified in the respective methods below, the column is hold at atemperature of 40° C. Flow from the column was brought to a MS detector.The MS detector was configured with an electrospray ionization source.The capillary needle voltage was 3 kV and the source temperature wasmaintained at 130° C. on the Quattro (triple quadrupole massspectrometer from Waters). Nitrogen was used as the nebulizer gas. Dataacquisition was performed with a Waters-Micromass MassLynx-Openlynx datasystem.

Method 6

In addition to the general procedure C: Reversed phase UPLC was carriedout on a Waters Acquity BEH (bridged ethylsiloxane/silica hybrid) C18column (1.7 μm, 2.1×100 mm) with a flow rate of 0.35 ml/min. Two mobilephases (mobile phase A: 95% 7 mM ammonium acetate/5% acetonitrile;mobile phase B: 100% acetonitrile) were employed to run a gradientcondition from 90% A and 10% B (hold for 0.5 minutes) to 8% A and 92% Bin 3.5 minutes, hold for 2 min and back to the initial conditions in 0.5min, hold for 1.5 minutes. An injection volume of 2 μl was used. Conevoltage was 20 V for positive and negative ionization mode. Mass spectrawere acquired by scanning from 100 to 1000 in 0.2 seconds using aninterscan delay of 0.1 seconds.

Method 7

In addition to the general procedure C: Reversed phase UPLC was carriedout on a Waters Acquity BEH (bridged ethylsiloxane/silica hybrid) C18column (1.7 μm, 2.1×100 mm) with a flow rate of 0.343 ml/min. Two mobilephases (mobile phase A: 95% 7 mM ammonium acetate/5% acetonitrile;mobile phase B: 100% acetonitrile) were employed to run a gradientcondition from 84.2% A and 15.8% B (hold for 0.49 minutes) to 10.5% Aand 89.5% B in 2.18 minutes, hold for 1.94 min and back to the initialconditions in 0.73 min, hold for 0.73 minutes. An injection volume of 2ml was used. Cone voltage was 20V for positive and negative ionizationmode. Mass spectra were acquired by scanning from 100 to 1000 in 0.2seconds using an interscan delay of 0.1 seconds.

General Procedure D

The HPLC measurement was performed using an Alliance HT 2795 (Waters)system comprising a quaternary pump with degasser, an autosampler, adiode-array detector (DAD) and a column as specified in the respectivemethods below, the column is hold at a temperature of 30° C. Flow fromthe column was split to a MS spectrometer. The MS detector wasconfigured with an electrospray ionization source. The capillary needlevoltage was 3 kV and the source temperature was maintained at 100° C. onthe LCT (Time of Flight Zspray mass spectrometer from Waters). Nitrogenwas used as the nebulizer gas. Data acquisition was performed with aWaters-Micromass MassLynx-Openlynx data system.

Method 8

In addition to the general procedure D: Reversed phase HPLC was carriedout on a Supelco Ascentis Express C18 column (2.7 μm, 3.0×50 mm) with aflow rate of 0.7 ml/min. Two mobile phases (mobile phase A: 100% 7 mMammonium acetate; mobile phase B: 100% acetonitrile) were employed torun a gradient condition from 80% A and 20% B (hold for 0.5 minute) to5% A and 95% B in 2.5 minutes, hold for 4.5 minutes and back to theinitial conditions in 1.5 minutes and hold for 1 min. An injectionvolume of 5 □l was used. Cone voltage was 20 V for positive and negativeionization mode. Mass spectra were acquired by scanning from 100 to 1000in 0.4 seconds using an interscan delay of 0.3 seconds.

TABLE A1 physico-chemical data If physio-chemical data were generatedmultiple times for a compound then all data is listed LC/ Melting KoflerHPLC GC/ Comp Point (K) or Rt MS MS No. (° C.) DSC (min) M+ (H⁺) method202 1.39 416 4 1.25 416 5  17 159 K 3.83 402 6 203 110 K 4.66 458 6 206101.91 DSC 4.15 460 6 207 126 K 3.41 459 6 126 K 126 K  56 147.56 DSC3.73 446 6 141.67 DSC 3.73 446 6 144 K 208 158 K 4.57 444 6 209 166.2DSC 4.14 422 6 210 176.79 DSC 3.89 434 6 176 K 211 187.05 DSC 3.79 446 6 1 152.97 DSC 3.12 406 6 152.4 DSC 3.12 406 6 154 K 212 145.81 DSC 3.8487 6 213 170.82 DSC 3.7 473 6 214 207.88 DSC 4.29 480 6 209 K 215 190 K3.8 416 6 216 162.91 DSC 3.54 556 6 22 108.61 DSC 4.52 414 6  60 90 K3.55 485 6 122 202.94 DSC 3.42 415 6  58 165 K 4.53 509 6 163.09 DSC  3168 K 3.22 420 6 145 K 3.23 420 6 218 204.29 DSC 3.59 448 6 219 215.88DSC 3.77 535 6 220 94.96 DSC 3.67 390 6 221 123.95 DSC 4.02 416 6 222142 K 4.23 404 6 223 3.69 501 6 224 128.96 DSC 3.6 427 6  62 220.78 DSC3.64 513 6 23 134 K 3.33 487 6 226 164.73 DSC 4.04 501 6  8 181 K 2.7419 6 185 K 2.75 419 6 179.61 DSC  84 from: DSC from 405 6 133.17 2.65to to 139.07 2.67 227 165.51 DSC 3.87 508 6  65 3.7 448 6 228 132 K 4.31400 6 229 123.16 DSC 4.01 529 6  73 3.5 499 6 231 106.81 DSC 3.72 565 6 59 200 K 4.08 563 6  52 159.08 DSC 3.99 474 6 232 3.84 381 6  64 2.31420 6 233 183.6 DSC 2.87 436 6 234 130 K 3.44 445 6 130 218 K 3.54 586 6DSC 2.76 586 7 235 154.8 DSC 3.37 515 6 154 K  69 260.14 DSC 2.8 4196 >260 K 2.84 419 6 263.87 DSC 236 1.28 438 5 1.28 438 5 237 80 K 4.44420 6 238 133.66 DSC 2.68 449 6  66 3.95 411 6  2 169.26 DSC 2.94 392 6169.13 DSC 2.94 392 6 113 177 K 3.27 420 6  68 165 K 2.86 415 6 239 160K 3.48 514 6 240 132 K 3.55 529 6 132.96 DSC 241 167.79 DSC 2.97 473 6149.64 DSC 2.96 473 6  55 3.9 543 6 242 196.25 DSC 3.53 429 6 243 146.13DSC 3.52 558 6 244 155 K 4 499 6 245 70 K 3.37 487 6 246 149.27 DSC 3.78531 6  24 80 K 3.44 446 6 249 2.63 477 6 250 104.64 DSC 4.13 545 6 251127.97 DSC 3.7 556 6  21 204.45 DSC 2.86 463 6 205.05 DSC 2.86 463 6  72120 K 3.67 513 6 253 167.45 DSC 3.5 503 6 254 173.43 DSC 3.77 517 6  74253 K 2.97 433 6  70a 163.31 DSC 2.86 459 6 256 171 K 3.69 457 6 173.42DSC  26 202.6 DSC 3.04 406 6 257 140.28 DSC 4.37 492 6  75 186.76 DSC2.87 436 6 186.1 DSC 2.87 436 6 2.87 436 6  7 3.31 463 6 259 163.47 DSC3.14 445 6 156 K 260 188.74 DSC 3.03 498 6  27 176.76 DSC 3.94 385 6  78162.1 DSC 3.38 434 6 161.7 DSC 3.38 434 6 165.99 DSC 3.17 434 8 261180.29 DSC 2.79 445 6 183 K 262 130.64 DSC 3.21 483 6  25 245.28 DSC2.96 445 6 259.39 DSC 2.96 445 6 263 168.45 DSC 3.74 473 6 264 3.14 4596 265 190 K 2.51 476 6 186.88 DSC 186.88 DSC 266 157.15 DSC 2.52 476 6 76 158.57 DSC 3.5 418 6 267 160.27 DSC 4.02 552 6 268 158.2 DSC 3.45512 6 177.91 DSC 3.46 512 6 269 155.79 DSC 4.46 444 6 271 181.91 DSC3.82 523 6 272 178.46 DSC 2.77 433 6 176.95 DSC 2.78 433 6 180 K 2732.73 540 6 274 176.3 DSC 4.45 456 6  4 from DSC From 447 6 134 or K 2.95to 142 to 2.99 276 188.62 DSC 3.12 512 6  28 142.35 DSC 2.98 450 6  37154.05 DSC 3.55 476 6 278 2.66 511 6 279 193.59 DSC 2.58 405 6 199 K 2812.55 503 6 283 128.64 DSC 2.87 487 6 79a + 79 2.81 489 6 602 158.84 DSC4.07 509 6  80 144 K 3.33 433 6  81 199 K 3.32 433 6 285 183.33 DSC 2.8459 6 2.83 459 6 286 114.64 DSC 3.24 473 6 114 K 287 156 K 3.49 445 6156.77 DSC  29 80 K 3.03 459 6 288 142 K 2.37 449 6 291 2.85 489 6 2933.96 390 6 294 184 K 2.52 391 6 2.54 391 6  16 80 K 3.21 432 6  20203.41 DSC 3.53 529 6 295 155.31 DSC 2.91 565 6 296 126.47 DSC 3.03 5036  54 138 K 3.93 342 6 297 140 K 2.45 434 6 298 2.41 489 6 299 201 DSC3.41 475 6  49 168.25 DSC 2.85 490 7  93 175.51 DSC 2.72 419 6 176.71DSC 2.62 419 6 302 222.79 DSC 2.77 503 6 303 194.82 DSC 2.8 474 6 304131.93 DSC 2.54 449 6 130 K 305 117.44 DSC 4.26 500 6  61 103.14 DSC3.57 459 6 306 185 K 3.07 477 6 182.27 DSC 307 132 K 3.33 473 6 168.8DSC 308 192 K 2.5 435 6 311 262.42 DSC 3.07 429 6 312 184.29 DSC 2.42477 6 313 176.49 DSC 2.95 477 6 176.31 DSC 2.96 477 6 314 201.43 DSC2.78 463 6 201 K  30 80 K 2.72 450 6  38 168 K 3.63 400 6 315 139 K 2.98424 6  48 189.27 DSC 3.27 497 6 316 158.73 DSC 3.51 526 6 320 193.76 DSC321 265.41 DSC 2.8 474 6  57 3.29 538 6 323 166.37 DSC 4.19 478 6  85DSC 4.16 448 6 324 144.1 DSC 3.6 473 6 3.6 473 6 325 2.76 516 6  86195.95 DSC 2.52 458 6 326 3.07 438 6  83 141.79 DSC 2.89 530 6 327 3.86434 6 329 2.87 488 6 330 139.15 DSC 2.96 502 6 332 141.98 DSC 2.92 475 6333 150 K 2.56 503 6 334 125 K 2.75 513 6 335 122.79 DSC 3.34 497 6 33660 K 3.9 442 6 3.9 442 6 338 198.91 DSC 2.6 405 6 339 187.62 DSC 2.3 5306 80 K  32 2.98 445 6 131 183.2 DSC 3.14 476 6 340 184.2 DSC 3.99 522 6342 228.85 DSC 3.7 487 6 343 80 (199) K 3.96 545 6 (6) 344 161.91 DSC3.06 477 6 (6)  31 244 K 2.93 459 6 250.38 DSC 2.93 459 6 254 K 345115.62 DSC 3.65 501 6 346 131.39 DSC 4.99 608 6 347 135 K 3.1 487 6 348169.44 DSC 3.8 503 6 350 0.83 562 5 351 110 K 2.89 516 6  89 126.66 DSC3.33 446 6 352 2.75 530 6  87 125 K 3.63 491 6 353 168 K 3.46 456 6 35470 K 4.05 458 6 355 184 K 4.44 486 6 184.23 DSC 356 154.94 DSC 3.71 4606  53 4.19 356 6  91 3.44 529 6  18 132 K 3.8 386 6 357 129.47 DSC 3.53503 6 358 114.12 DSC 4.37 486 6 110 K 359 114.97 DSC 4.34 486 6 126 K360 133.89 DSC 4.15 452 6 130 K 361 188 K 2.87 473 6 362 80 K 3.77 501 6363 172.65 DSC 2.69 511 6 175.38 DSC 2.68 511 6 364 2.94 488 6 2.91 4886 365 164.92 DSC 2.83 433 6 366 3.21 501 6 367 3.17 487 6 300 193.25 DSC3.4 480 6 191.77 DSC 3.4 480 6 191.77 DSC 3.4 480 6 368 2.63 497 6 3693.4 480 6 370 94 K 3.51 459 6 372 176.98 DSC 3.3 556 6  92 148.61 DSC3.67 515 6 138.58 DSC 3.6 515 6 148.29 DSC 3.6 515 6 373 165 K 2.34 4356 374 206.48 DSC 3.65 525 6 375 188.66 DSC 3.61 501 6 229.66 DSC 3.61501 6 376 214.67 DSC 3.5 586 6 377 112.31 DSC 3.89 495 6 378 3.25 531 63.26 531 6 379 80 K 2.8 488 6 146.1 DSC 2.83 488 6 380 70 K 2.54 449 6381 132.63 DSC 3.98 512 6 382 118 K 2.91 461 6 113 K 2.94 461 6 109.12DSC 2.95 461 6 112.07 DSC 104.44 DSC 132 132.47 DSC 3.31 487 6 130.95DSC 3.31 487 6 138 K 383 120 DSC 2.92 503 6 2.91 503 6 384 80 K 2.99 4896 385 119.77 DSC 4.93 488 6  39 4.33 501 6  40 4.66 501 6 133 126.47 DSC3.55 484 6 125.21 DSC 3.55 484 6 386 80 K 2.98 544 6 387 162.58 DSC 2.45466 6 389 156.45 DSC 3.75 448 6 160 K 390 3.7 498 6 391 190 K 2.63 475 6393 193.78 DSC 3.22 410 6 395 118.99 DSC 2.83 475 6  94 115.24 DSC 3.1443 6 3.11 443 6 396 156 K 3.14 487 6 397 132.82 DSC 3.24 450 6 398 2.96473 6 399 3.12 409 6 400 3.12 409 6 401 138 K 3.47 408 6 405 191.73 DSC3.01 406 6 407 146 K 4.37 412 6 408 130 K 4.1 444 6 410 2.83 477 6 4118.92 458 2 5.93 458 1 412 180 K 2.85 489 6 413 146 K 3.03 507 6 414 3.1451 6 422 234.9 DSC 3.28 420 6 424 3.16 440 6 426 2.82 447 6 428 0.56432 5 34 173.67 DSC 2.46 462 6 430 3.78 498 6 125 99.31 DSC 2.58 435 6431 147.77 DSC 3.99 509 6 432 251.77 DSC 2.79 436 6 433 2.39 423 6 4342.96 487 6 435 2.89 447 6  5 from DSC 3.63 501 8 123.12 or K to or 6 to128 3.91 436 2.86 489 6 95a + 95 3.49 559 6 437 2.66 433 6 438 140.67DSC 2.44 391 6 440 2.9 437 6 441 3.04 481 6 442 120.06 DSC 3.39 461 6443 138.47 DSC 2.94 450 6 444 137.16 DSC 2.95 450 6 445 182.81 DSC 3.31473 6 227.95 DSC 227.75 DSC 447 3.05 447 6 448 80 K 3.6 470 6 449 118.96DSC 3.05 447 6 450 224.87 DSC 3.6 470 6 452 3.13 461 6 453 3.04 396 6134 184 DSC 2.71 504 6 194 K 2.72 504 6 454 244.06 DSC 3.25 545 8 455155 K 3.13 586 8 456 143.58 DSC 2.9 502 8  96 168.08 DSC 2.94 501 8 4573.2 571 6 458 171.31 DSC 3.34 470 6 44a + 44 215.29 DSC 3.84 495 6 45999.32 DSC 4.23 593 6 460 3.14 438 6 463 3.72 568 6 464 4.39 555 6 465141.31 DSC 2.91 473 6 467 135 K 2.89 503 6 468 130 K 2.84 503 6 469 135K 3.05 487 6 471 140 K 3.14 489 6 473 140 K 3.14 489 6 474 3.56 590 6135 194 DSC K 3.13 461 6 475 152.98 DSC 3.18 420 6 476 170.9 DSC 3.6 4486 477 80 K 3.05 380 6 478 70 K 2.93 407 6 136 166 DSC 3.14 531 6 480 DSC3.13 515 6  97 187.39 DSC 2.87 436 6 187.8 DSC 2.87 436 6  98 186.98 DSC2.87 436 6 186.27 DSC 2.87 436 6 481 172.5 DSC 3.67 474 6 482 106 K 2.82419 6 483 134 K 3.01 433 6 484 3.03 461 6 485 0.62 474 5 487 143.13 DSC4.82 488 1 488 96.65 DSC 2.73 393 6 2.73 393 6 489 128.03 DSC 3.4 551 6490 223.8 DSC 2.63 449 6 493 87.6 DSC 3.05 435 6 494 135.12 DSC 3.02 4476 495 3.83 486 6 137 2.8 433 6 499 130 K 3.34 501 6 500 0.69 421 5 501154.26 DSC 2.63 449 6 502 153.17 DSC 2.65 449 6 503 3.48 511 6 139 3.53517 6 504 101.17 DSC 2.53 476 6 104.18 DSC 2.53 476 6 140 123.19 DSC3.25 458 6 128.99 DSC 3.26 458 6 506 3.42 463 6 507 3.36 463 6 508165.94 DSC 3.49 446 6 509 3.42 634 6 510 70 K 2.77 407 6 141 150 K 3.29448 8 171.28 DSC 3.54 448 6 156.7 DSC 511 0.74 502 5 512 180 K 3.41 4736 513 160.65 DSC 3.55 469 6 514 139 K 3.3 489 6 135.37 DSC 515 4.78 5163 516 0.98 471 5 1.08 471 4 35 0.92 416 5 517 187.18 DSC 518 187.66 DSC3.01 479 6 519 163.93 DSC 3.08 516 6 102 0.89 487 4 521 0.91 475 5 522134.16 DSC 2.99 503 6 523 125.77 DSC 3.53 517 6 142 126.8 DSC 3.53 517 6524 122.12 DSC 3 433 6 525 223.34 DSC 3.32 514 6 526 234.8 DSC 3.32 5146 527 144 K 3.19 484 6 145.21 DSC 143 184.72 DSC 3.15 516 6 528 110.16DSC 2.86 518 6 529 141.1 DSC 3.06 459 6 530 132.62 DSC 2.96 488 6 132.62DSC  10 4.28 551 6 531 3.53 489 6  36 160.14 DSC 3.38 418 6 532 164 K3.06 470 6 165 DSC 533 180.45 DSC 2.71 449 6 181.17 DSC 534 205.99 DSC3.6 475 6 535 180 K 3.4 473 6 179.19 DSC 536 209.5 DSC 3.72 461 6 537201.67 DSC 3.7 461 6 538 4.04 390 6 144 225.35 DSC 2.96 488 6 222 K 5390.64 473 5 603 1.01 5 540 130.63 DSC 3.19 505 6 541 162.74 DSC 2.99 5306 542 147.16 DSC 3.85 487 6 155 K 543 149.47 DSC 3.04 517 6 544 3.43 5426  41 168 K 2.86 437 6 169.24 DSC  33 83 K 3.02 501 6  43 107 K 3.08 5016 546 135 K 3.13 501 6 547 217 K 3.22 473 6 548 135 K 3.13 501 6 5511.02 515 5 552 0.87 500 4 0.63 500 5 553 3.22 489 6 554 3.48 491 6 5562.72 396 6 557 189 K 3.42 470 6 558 94 K 3 449 6 103 140 K 3.94 512 6559 98.59 DSC 2.79 477 6 145 94.44 DSC 2.8 477 6 129 1.1 495 4 1.13 4955 111 1.27 593 5 1.33 593 4 1.27 593 5 1.27 593 5 1.28 593 5 560 0.74547 5 561 219 K 3.19 475 6 562 3.8 487 6 563 193 K 3.2 498 6 200.75 DSC564 2.99 567 6 565 152 K 3.34 408 6 566 183 K 3.09 484 6 567 3.1 484 6568 164.5 DSC 3.4 453 6 167 K 569 139 K 3.38 453 6 139.45 DSC 146 163 K3.36 454 6 158.48 DSC 110 0.78 503 5 570 0.88 489 5 575 0.71 475 5 5761.36 579 5 577 3.57 487 6 578 3.5 485 6 581 3.17 501 6 582 127 K 4.03489 6 583 136.49 DSC 3 599 6 584 140 K 4.07 531 6 585 2.87 488 6 5863.82 471 6 105 135 K 3.94 512 6 147 4.25 529 6 592 194 K 2.89 421 6 593168 K 4.01 502 6 148 149.13 DSC 3.67 474 6 149 146.61 DSC 3.67 474 6 10073 K 3.63 549 6 3.63 549 6 101 186 K 3.16 456 6 14 + 14a 110 K 3.62 4786 594 214.83 DSC 595 105 K 3.13 470 8  15 114.76 DSC 3.62 487 6 604 157DSC 3.16 489 608 159 DSC 2.66 419 8 609 155 DSC 2.65 419 8 610 150 DSC2.66 419 8 611 148 DSC 2.68 419 8 697 171 DSC 2.97 461 6 698 111 DSC3.03 461 6 699 150 DSC 2.99 461 6 700 133 DSC 2.85 477 7 613 1.26 402 4701 68 DSC 3.18 503 6 702 129 DSC 3.89 501 6 703 80 K 3.92 501 6 645 188DSC 2.44 433 6 704 151 DSC 3.74 487 6 615 134 DSC 2.62 519 6 646 125 K2.51 392 6 648 196 DSC 3.42 515 6 705 135 DSC 3.3 487 6 706 182 K 2.58392 6 707 186 K 2.23 391 6 647 133 K 2.3 419 6 708 152 K 3.1 473 6 709175 K 3.25 544 6 710 206 DSC 3.24 461 6 711 166 DSC 3.15 426 6 712 124DSC 3.02 376 6 616 170 K 2.42 246 6 713 127 K 3.83 507 6 619 210 K 3.07505 6 714 128 K 3.62 477 6 690 138 K 3.63 477 6 716 247 DSC 2.81 417 6717 125 DSC 3.59 483 6 718 103 DSC 3.66 501 6 719 119 DSC 4.59 509 6 720175 DSC 721 0.67 528 4 722 138 K 3.57 455 6 724 176 DSC 3.07 433 6 620114 K 3.89 587 6 725 227 DSC 3.11 474 6 727 109 DSC 3.01 461 6 728 109DSC 3.77 497 6 621 >260 K 2.7 486 6 729 183 DSC 2.99 515 6 730 139 K 3.4501 6 731 237 DSC 339 478 6 732 160 K 3.46 458 6 733 70 K 734 178 K 3.97507 6 624 147 K 2.65 475 6 735 143 DSC 3.56 408 6 736 68 K 2.39 450 7625 104 K 3.06 575 7 737 156 DSC 2.28 489 7 652 142 DSC 2.84 507 7 65066 K 2.98 616 7 738 197 DSC 2.99 502 7 739 179 DSC 2.99 502 7 740 167DSC 2.97 483 7 651 122 K 2.05 516 7 617 149 DSC 2.44 416 7 741 85 K 3.34506 7 742 115 K 3.2 507 7 618 139 DSC 2.3 457 7 743 135 DSC 2.83 481 7744 200 K 2.23 530 7 745 110 K 3.36 476 7 746 62 K 2.44 464 7 747 68 K2.67 507 7 689 203 DSC 2.77 492 7 749 86 K 2.64 448 7 622 190 K 2.57 4347 688 175 DSC 6.04 508 7 750 148 DSC 2.61 493 7 655 8.11 506 10 751 2.99585 7 752 169 K 3.01 502 7 753 155 DSC 3.01 491 7 754 167 K 2.19 499 7755 152 K 2.72 434 7 756 118 K 2.23 461 7 757 126 K 2.64 461 7 758 2.22485 7 653 146 DSC 311 511 7 759 180 K 2.85 502 7 760 221 K 2.51 507 7623 133 K 2.43 475 7 761 119 K 3.2 515 7 762 137 K 3.18 507 7 763 176 K2.27 463 7 764 126 K 2.56 475 7 765 199 DSC 2.65 492 7 766 125 DSC 2.93507 7 767 220 K 2.9 527 7 768 158 DSC 2.79 515 7 770 130 K 2.27 477 7644 96 K 2.06 603 7 656 95 K 2.83 478 7 657 110 K 2.83 478 7 658 152 DSC3.19 552 7 771 93 K 2.56 492 7 772 154 DSC 2.84 493 7 773 2.3 504 7 77480 K 3 513 7 627 2.2 471 7 775 133 K 2.51 432 7 776 6.62 428 9 777 119DSC 3.11 535 7 778 148 K 3.13 516 7 779 148 K 3.13 516 7 628 122 K 2.84492 7 629 124 K 2.84 492 7 780 188 K 3.12 502 7 781 186 K 3.12 502 7 782170 K 4.31 617 7 634 80 K 621 491 7 783 220 K 6.05 468 7 784 163 DSC2.61 493 7 785 190 K 2.83 575 7 786 125 DSC 2.79 492 7 787 181 DSC 2.95503 7 788 146 K 2.57 507 7 789 204 K 2.49 520 7 790 67 K 3.47 583 7 791130 K 2.94 576 7 792 153 DSC 2.82 478 7 793 161 DSC 3 508 7 631 194 DSC2.39 483 7 794 2.6 500 7 795 182 K 2.95 507 7 796 189 DSC 3.04 508 7 7973.18 443 8 798 2.62 486 7 659 106 DSC 3.05 484 7 662 122 K 3.07 512 7799 114 DSC 3.05 510 7 661 154 DSC 2.47 518 7 660 151 DSC 2.47 518 7 633130 DSC 2.69 477 7 800 134 DSC 3.05 512 7 801 127 DSC 3.21 514 7 802 80K 2.19 493 7 803 80 K 2.19 493 7 636 80 K 3.35 493 7 637 >260 K 3.07 4937 804 195 DSC 3.1 522 7 805 156 DSC 2.91 535 7 806 182 K 3.19 536 7 80796 K 3.01 509 7 808 162 DSC 3.25 509 7 809 150 DSC 2.93 506 7 810 131DSC 2.76 482 7 635 111 DSC 3.11 495 7 811 127 DSC 3.08 511 7 812 170 DSC2.65 454 7 813 166 K 2.4 442 7 814 160 DSC 2.98 495 7 815 123 DSC 3.24483 7 816 176 DSC 3.12 555 7 817 155 DSC 3.01 491 7 640 241 DSC 2.71 5067 819 80 K 2.96 480 7 687 162 DSC 2.23 483 7 820 161 DSC 3.11 545 7 632157 DSC 2.59 430 7 821 127 K 296 537 7 822 135 K 2.78 436 7 823 218 DSC2.53 526 7 824 212 DSC 2.82 510 7 825 237 DSC 2.55 492 7 826 202 DSC2.74 543 7 827 187 DSC 2.82 544 7 828 209 DSC 2.56 468 7 829 154 DSC3.24 536 7 830 241 DSC 2.65 527 7 663 200 DSC 2.38 498 7 664 80 K 2.77469 7 831 178 DSC 2.84 536 7 832 111 DSC 3.67 482 7 833 153 DSC 2.79 4937 834 198 DSC 2.63 475 7 835 144 DSC 3.24 552 7 837 2.63 472 7 641 155 K2.27 476 7 642 127 DSC 2.36 486 7 838 171 DSC 2.28 462 7 839 126 DSC3.49 567 7 840 158 DSC 2.44 517 7 841 3.08 463 7 842 154 DSC 3.24 553 7665 206 K 3.3 516 7 643 160 K 2.4 503 7 836 2.57 496 7 606 142 K 3.25420 6 666 163 K 2.68 516 7 844 125 K 2.68 530 7 845 167 DSC 3.18 512 7846 170 K 2.49 477 6 847 0.79 435 5 667 181 DSC 3.07 471 7 848 223 K3.13 496 7 849 80 K 3.11 453 7 850 142 DSC 3.67 513 7 851 137 DSC 4 5437 669 122 DSC 3.55 526 7 852 233 K 3.43 496 7 853 254 K 3.12 496 7 670157 K 3.03 461 6 855 1.01 501 4 0.86 501 5 696 188 K 3.07 456 6 856 97 K2.96 482 6 857 180 K 3.43 487 6 671 144 DSC 2.97 501 6 858 154 K 3.58470 6 673 181 DSC 3.76 482 6 180 K 676 88 K 3.71 503 6 859 80 K 3.22 4856 860 151 DSC 3.21 485 6 678 148 DSC 2.27 539 7 2.87 539 6 680 167 DSC2.58 460 6 861 156 K 3.22 447 6 691 99 DSC 2.17 477 7 2.73 477 6 862 178K 3.44 573 6 682 149 K 2.86 461 6 863 170 K 3.77 462 6 864 154 K 3.77462 6 865 146 DSC 3.81 498 6 866 144 DSC 3.81 498 6 679 2.99 491 6 693151 DSC 2.79 502 6 867 178 K 2.98 424 6 868 178 K 2.98 424 6 694 197 DSC3.49 501 6 869 138 K 3.46 489 6 692 157 K 3.19 498 6 675 187 K 3.44 5176 870 173 K 3.34 456 6 685 203 K 3.17 442 6 871 154 DSC 3.05 450 6 87289 DSC 4.08 515 6 677 177 DSC 3.44 435 6 873 183 DSC 3.07 457 6 874 107K 3.24 450 6 875 98 K 3.24 450 6 877 213 DSC 2.94 500 6 878 143 DSC 3.52503 6 879 0.89 531 5 880 135 DSC 3.45 501 6 668 137 DSC 672 194 DSC 683123 DSC 881 156.5 DSC 4.53 440 6 882 164 K 4.46 454 6 883 194 DSC 4.35399 6 884 80 K 3.58 483 6 885 148 DSC 5.13 640 6 886 130 K 3.97 455 6887 245 DSC 2.81 457 6 888 2.96 500 6 889 0.6 5 890 6.18 444 1 891 186 K3.89 489 6 892 157 K 4.32 534 6 893 1.05 443 4 894 3.58 489 6 895 182DSC 3.56 470 6 896 166 DSC 2.74 419 6 897 153 DSC 2.75 419 6 898 6.24430 1 899 3.6 480 6 900 214 DSC 3.47 475 6 901 208 DSC 3.02 433 6902 >260 K 2.34 470 6 903 153 DSC 3.65 513 6 904 181 DSC 3.07 471 6 9050.98 457 5 906 2.83 517 6 907 2.97 491 7 908 3.19 501 7 909 2.99 491 7910 3.18 501 7 911 3.13 501 7 912 102 K 2.89 474 7 913 170 K 3.1 538 7914 166 K 3.01 599 7 915 3.22 542 7 916 70 K 3.53 552 7 917 222 DSC 2.73517 7 918 3.36 496 7 919 130 DSC 3.5 490 7 920 123.5 DSC 3.39 541 7 921123 DSC 3.07 493 7 922 123 DSC 3.07 493 7 927 152 K 2.52 483 7 928 130 K5.42 442 9

NMR Data

The below NMR experiments were carried out using a Bruker Avance 500 anda Bruker Avance DRX 400 spectrometers at ambient temperature, usinginternal deuterium lock and equipped with reverse triple-resonance (¹H,¹³C,¹⁵N TXI) probe head for the 500 MHz and with reversedouble-resonance (¹H, ¹³C, SEI) probe head for the 400 MHz. Chemicalshifts (δ) are reported in parts per million (ppm).

Compound 131

¹H NMR (500 MHz, DMSO-d₆) δ 9.01 (s, 1H), 8.60 (s, 1H), 8.28 (s, 1H),7.79 (d, J=9.1 Hz, 1H), 7.27 (dd, J=2.5, 9.1 Hz, 1H), 7.16 (d, J=2.5 Hz,1H), 6.38-6.49 (m, 3H), 4.82 (br. s., 2H), 4.23 (t, J=5.7 Hz, 2H), 3.96(t, J=4.9 Hz, 2H), 3.80 (t, J=5.7 Hz, 2H), 3.71-3.75 (m, 5H), 3.69 (t,J=4.9 Hz, 2H), 1.05-1.26 (m, 1H), 0.42-0.51 (m, 2H), 0.16-0.25 (m, 2H)

Compound 149

¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.58 (s, 1H), 8.22 (s, 1H),7.80 (d, J=9.1 Hz, 1H), 7.31 (dd, J=2.5, 9.1 Hz, 1H), 7.25 (d, J=2.5 Hz,1H), 6.80 (br. s., 1H), 6.49 (d, J=1.9 Hz, 2H), 6.42 (br. s., 1H),4.15-4.31 (m, 2H), 3.89-4.00 (m, 4H), 3.74 (s, 6H)

Compound 148

¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.58 (s, 1H), 8.22 (s, 1H),7.80 (d, J=9.1 Hz, 1H), 7.31 (dd, J=2.5, 9.1 Hz, 1H), 7.25 (d, J=2.5 Hz,1H), 6.80 (br. s., 1H), 6.49 (d, J=1.9 Hz, 2H), 6.42 (br. s., 1H),4.15-4.31 (m, 2H), 3.89-4.00 (m, 4H), 3.74 (s, 6H)

Compound 147

¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (br. s., 1H), 9.01 (s, 1H), 8.64 (s,1H), 8.22 (s, 1H), 7.79 (d, J=9.3 Hz, 1H), 7.26 (dd, J=2.8, 9.3 Hz, 1H),7.18 (d, J=2.8 Hz, 1H), 6.36-6.51 (m, 3H), 4.58 (spt, J=6.6 Hz, 1H),4.03-4.19 (m, 2H), 3.93 (t, J=7.3 Hz, 2H), 3.75 (s, 6H), 3.09-3.20 (m,2H), 2.08 (td, J=7.3, 14.5 Hz, 2H), 1.49 (d, J=6.6 Hz, 6H)

Compound 146

¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.71 (s, 1H), 8.65 (t, J=1.5Hz, 1H), 8.51-8.56 (m, 2H), 8.19 (s, 1H), 7.79 (d, J=9.1 Hz, 1H), 7.39(dd, J=2.8, 9.1 Hz, 1H), 7.22 (d, J=2.8 Hz, 1H), 6.55 (d, J=2.1 Hz, 2H),6.37 (t, J=2.1 Hz, 1H), 5.31 (s, 2H), 3.91 (s, 3H), 3.72 (s, 6H)

Compound 145

¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (br. s., 2H), 8.55 (s, 1H), 8.20 (s,1H), 7.79 (d, J=9.1 Hz, 1H), 7.34 (dd, J=2.6, 9.1 Hz, 1H), 7.26 (d,J=2.6 Hz, 1H), 6.55 (d, J=1.9 Hz, 2H), 6.43 (s, 1H), 4.17 (br. s., 1H),3.88-3.99 (m, 6H), 3.75 (s, 6H), 3.30 (td, J=6.3, 11.9 Hz, 1H),3.02-3.16 (m, 1H), 2.96 (q, J=9.6 Hz, 1H), 1.22 (d, J=6.3 Hz, 6H)

Compound 144

¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (s, 1H), 8.55 (s, 1H), 8.21 (s, 1H),7.77 (d, J=9.5 Hz, 1H), 7.73 (br. s., 1H), 7.27 (dd, J=2.7, 9.5 Hz, 1H),7.14 (d, J=2.7 Hz, 1H), 6.45 (d, J=2.2 Hz, 2H), 6.38-6.41 (m, 1H), 3.99(t, J=6.6 Hz, 2H), 3.93 (s, 3H), 3.73 (s, 6H), 3.14 (br. s., 2H), 3.01(s, 2H), 2.68 (t, J=6.6 Hz, 2H), 2.63 (t, J=5.2 Hz, 2H)

Compound 143

¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (s, 1H), 8.55 (s, 1H), 8.21 (s, 1H),7.77 (d, J=9.1 Hz, 1H), 7.28 (dd, J=2.5, 9.1 Hz, 1H), 7.14 (d, J=2.5 Hz,1H), 6.44 (d, J=2.2 Hz, 2H), 6.32-6.42 (m, 1H), 3.98 (t, J=6.9 Hz, 2H),3.93 (s, 3H), 3.73 (s, 6H), 3.35-3.43 (m, 4H), 2.63 (t, J=6.9 Hz, 2H),2.44 (t, J=4.9 Hz, 2H), 2.38 (t, J=4.9 Hz, 2H), 1.97 (s, 3H)

Compound 142

¹H NMR (500 MHz, DMSO-d₆) δ 8.95 (s, 1H), 8.55 (s, 1H), 8.20 (s, 1H),7.75 (d, J=9.5 Hz, 1H), 7.34 (dd, J=2.7, 9.5 Hz, 1H), 7.22 (d, J=2.7 Hz,1H), 6.49 (d, J=1.9 Hz, 2H), 6.38 (t, J=1.9 Hz, 1H), 5.16 (d, J=5.1 Hz,1H), 3.83-4.00 (m, 5H), 3.69-3.78 (m, 7H), 3.19-3.31 (m, 2H), 2.68-2.78(m, 1H), 2.66 (td, J=6.1, 12.1 Hz, 1H), 2.30-2.40 (m, 1H)

Compound 141

¹H NMR (500 MHz, DMSO-d₆) δ 8.95 (s, 1H), 8.55 (s, 1H), 8.21 (s, 1H),7.76 (d, J=9.1 Hz, 1H), 7.26 (dd, J=2.5, 9.1 Hz, 1H), 7.14 (d, J=2.5 Hz,1H), 6.34-6.44 (m, 3H), 4.49 (s, 1H), 3.84-3.99 (m, 5H), 3.74 (s, 6H),1.66-1.86 (m, 2H), 1.16 (s, 6H)

Compound 140

¹H NMR (500 MHz, DMSO-d₆) δ 8.95 (s, 1H), 8.55 (s, 1H), 8.20 (s, 1H),7.76 (d, J=9.1 Hz, 1H), 7.28 (dd, J=2.5, 9.1 Hz, 1H), 7.14 (d, J=2.5 Hz,1H), 6.46 (d, J=1.9 Hz, 2H), 6.41 (t, J=1.9 Hz, 1H), 3.83-3.96 (m, 5H),3.74 (s, 6H), 2.82 (t, J=6.7 Hz, 2H), 2.78 (t, J=6.7 Hz, 2H), 2.57 (t,J=6.7 Hz, 2H), 2.22 (br. s., 1H)

Compound 139

¹H NMR (500 MHz, DMSO-d₆) δ 8.95 (s, 1H), 8.55 (s, 1H), 8.20 (s, 1H),7.75 (d, J=9.5 Hz, 1H), 7.34 (dd, J=2.7, 9.5 Hz, 1H), 7.22 (d, J=2.7 Hz,1H), 6.49 (d, J=1.9 Hz, 2H), 6.38 (t, J=1.9 Hz, 1H), 5.16 (d, J=5.1 Hz,1H), 3.83-4.00 (m, 5H), 3.69-3.78 (m, 7H), 3.19-3.31 (m, 2H), 2.68-2.78(m, 1H), 2.66 (td, J=6.1, 12.1 Hz, 1H), 2.30-2.40 (m, 1H)

Compound 137

¹H NMR (400 MHz, DMSO-d₆) δ 9.10 (br.s., 3H), 8.49 (s, 2H), 7.84 (d,J=9.6 Hz, 1H), 7.39 (dd, J=2.7, 9.6 Hz, 1H), 7.29 (d, J=2.7 Hz, 1H),6.52 (d, J=2.1 Hz, 2H), 6.46 (t, J=2.1 Hz, 1H), 4.21 (t, J=7.3 Hz, 2H),3.76 (s, 6H), 3.35 (m, 1H), 3.15 (br. s., 2H), 1.25 (d, J=6.1 Hz, 6H)

Compound Number 98

¹H NMR (500 MHz, DMSO-d₆) δ 8.95 (s, 1H), 8.56 (s, 1H), 8.21 (s, 1H),7.75 (d, J=9.1 Hz, 1H), 7.34 (dd, J=2.5, 9.1 Hz, 1H), 7.25 (d, J=2.5 Hz,1H), 6.50 (d, J=2.2 Hz, 2H), 6.37 (t, J=2.2 Hz, 1H), 5.01 (d, J=2.8 Hz,1H), 4.70-4.79 (m, 1H), 4.03 (dd, J=3.6, 14.9 Hz, 1H), 3.92 (s, 3H),3.81 (br. s., 1H), 3.73 (s, 6H), 3.68 (dd, J=8.1, 14.9 Hz, 1H),3.36-3.48 (m, 2H)

Compound 136

¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (br.s., 2H), 8.58 (s, 1H), 8.25 (s,1H), 7.83 (d, J=9.5 Hz, 1H), 7.36 (dd, J=2.5, 9.5 Hz, 1H), 7.23 (d,J=2.5 Hz, 1H), 6.52 (d, J=1.9 Hz, 2H), 6.46 (t, J=1.9 Hz, 1H), 4.19-4.21(m, 2H), 4.10 (d, J=6.9 Hz, 2H), 3.84 (dd, J=2.8, 11.7 Hz, 2H), 3.76 (s,6H), 3.31-3.38 (td, J=6.1, 11.7, 1H), 3.27 (t, J=11.7 Hz, 2H), 3.14-3.18(m, 2H), 2.16-2.08 (m, 1H), 1.43 (d, J=11.7 Hz, 2H), 1.18-1.37 (m, 8H)

Compound 135

¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (br.s., 2H), 8.62 (s, 1H), 8.23 (s,1H), 7.83 (d, J=9.5 Hz, 1H), 7.36 (dd, J=2.5, 9.5 Hz, 1H), 7.25 (d,J=2.5 Hz, 1H), 6.51 (d, J=2.2 Hz, 2H), 6.46 (t, J=2.2 Hz, 1H), 3.76 (s,6H), 4.12-4.27 (m, 4H), 3.30-3.43 (m, 1H), 3.07-3.19 (m, 2H), 1.44 (t,J=7.2 Hz, 3H), 1.25 (d, J=6.3 Hz, 6H)

Compound 134

¹H NMR (500 MHz, DMSO-d₆) δ 9.05 (s, 1H), 8.93 (m, 1H), 8.57 (s, 1H),8.25 (s, 1H), 8.18 (q, J=4.6 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.33 (dd,J=2.5, 9.1 Hz, 1H), 7.28 (d, J=2.5 Hz, 1H), 6.52 (d, J=2.2 Hz, 2H), 6.46(t, J=2.2 Hz, 1H), 4.88 (s, 2H), 4.19 (t, J=7.6 Hz, 2H), 3.75 (s, 6H),3.29-3.42 (m, 1H), 3.16 (br. s., 2H), 2.64 (d, J=4.6 Hz, 3H), 1.25 (d,J=6.6 Hz, 6H)

Compound Number 5

¹H NMR (500 MHz, DMSO-d₆) δ 8.95 (s, 1H), 8.55 (s, 1H), 8.20 (s, 1H),7.75 (d, J=9.1 Hz, 1H), 7.28 (dd, J=2.5, 9.1 Hz, 1H), 7.12 (d, J=2.5 Hz,1H), 6.40 (s, 3H), 3.93 (s, 3H), 3.88 (t, J=7.1 Hz, 2H), 3.74 (s, 6H),3.11-3.28 (m, 2H), 2.68-2.72 (m, 2H), 2.39-2.48 (m, 1H), 1.78 (quin,J=7.1 Hz, 2H)

Compound 133

¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.56 (s, 1H), 8.21 (s, 1H),7.77 (d, J=9.5 Hz, 1H), 7.27 (dd, J=2.5, 9.5 Hz, 1H), 7.12 (d, J=2.5 Hz,1H), 6.29-6.49 (m, 3H), 3.96 (t, J=6.8 Hz, 2H), 3.93 (s, 3H), 3.74 (s,6H), 3.19-3.29 (m, 1H), 2.70-2.85 (m, 5H), 2.42-2.46 (m, 1H), 2.10-2.24(m, 1H), 1.88-1.98 (m, 1H)

Compound 132

¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (s, 1H), 8.55 (s, 1H), 8.20 (s, 1H),7.76 (d, J=9.3 Hz, 1H), 7.23 (dd, J=2.8, 9.3 Hz, 1H), 7.07 (d, J=2.8 Hz,1H), 6.41 (s, 3H), 3.93 (s, 3H), 3.81 (t, J=7.4 Hz, 2H), 3.74 (s, 6H),3.23-3.32 (m, 4H), 2.23 (t, J=8.1 Hz, 2H), 1.93 (m, 2H), 1.84 (m, 2H)

Compound Number 300

¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (s, 1H), 8.54-8.63 (m, 1H), 8.24 (s,1H), 7.84 (d, J=9.1 Hz, 1H), 7.41 (d, J=2.5 Hz, 1H), 7.34 (dd, J=2.5,9.1 Hz, 1H), 7.20 (s, 1H), 6.88 (s, 1H), 6.50 (s, 2H), 6.42-6.47 (m,1H), 4.99 (s, 2H), 3.93 (s, 3H), 3.74 (s, 6H), 3.53 (s, 3H)

Compound Number 4

¹H NMR (500 MHz, DMSO-d₆) δ 8.95 (s, 1H), 8.55 (s, 1H), 8.20 (s, 1H),7.76 (d, J=9.1 Hz, 1H), 7.27 (dd, J=2.8, 9.1 Hz, 1H), 7.13 (d, J=2.8 Hz,1H), 6.46 (d, J=2.2 Hz, 2H), 6.40 (t, J=2.2 Hz, 1H), 3.93 (s, 3H), 3.88(t, J=6.9 Hz, 2H), 3.74 (s, 6H), 2.79 (t, J=6.9 Hz, 2H), 2.70 (m, 1H),1.69 (br. s., 1H), 0.95 (d, J=6.3 Hz, 6H)

Compound Number 84

¹H NMR (500 MHz, DMSO-d₆) δ 8.94 (s, 1H), 8.55 (s, 1H), 8.20 (s, 1H),7.75 (d, J=9.3 Hz, 1H), 7.28 (dd, J=2.5, 9.30 Hz, 1H), 7.15 (d, J=2.5Hz, 1H), 6.45 (d, J=2.2 Hz, 2H), 6.38-6.42 (m, 1H), 3.93 (s, 3H), 3.82(t, J=7.1 Hz, 2H), 3.74 (s, 6H), 2.80 (t, J=7.1 Hz, 2H), 1.55 (br. s.,2H)

Compound 130

¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.69 (s, 1H), 8.33 (s, 1H),7.79 (d, J=9.5 Hz, 1H), 7.28 (dd, J=2.7, 9.5 Hz, 1H), 7.14 (d, J=2.7 Hz,1H), 6.38-6.47 (m, 3H), 5.55 (br.s., 1H), 4.34 (t, J=6.6 Hz, 2H),3.62-3.91 (m, 12H), 3.36-3.55 (m, 6H), 3.09-3.31 (m, 4H), 2.28-2.38 (m,2H), 1.75-1.97 (m, 2H), 1.10-1.23 (m, 1H), 0.43-0.52 (m, 2H), 0.15-0.24(m, 2H)

The below NMR experiments were carried out using a Bruker Avance AV400spectrometer, using an internal deuterium lock and equipped with a4-nucleus (¹H, ¹³C, ¹⁹F, ³¹P) probe head. Chemical shifts (6) arereported in parts per million (ppm) at 27° C.

Compound 138

¹H NMR (400 MHz, DMSO-d₆): 9.07 (1H, s), 8.59 (1H, s), 8.56-8.47 (1H,m), 8.27-8.21 (1H, m), 7.87 (1H, d), 7.54-7.47 (1H, m), 7.43-7.32 (3H,m), 7.27-7.18 (1H, m), 3.98-3.89 (3H, m), 3.83 (2H, d), 2.76 (3H, d),1.23-1.13 (1H, m), 0.50-0.41 (2H, m), 0.22-0.14 (2H, m).

Compound Number 99

¹H NMR (400 MHz, Me-d₃-OD): 8.89 (1H, s), 8.40 (1H, s), 8.23 (1H, s),7.79 (1H, d), 7.41 (1H, dd), 7.30 (1H, d), 7.01 (2H, s), 6.53 (2H, s),6.47-6.40 (1H, m), 4.57 (2H, s), 4.01 (3H, s), 3.77 (7H, s).

Compound 200

¹H NMR (400 MHz, DMSO-d₆): 8.96 (1H, s), 8.56 (1H, s), 8.21 (1H, s),7.76 (1H, d), 7.25 (1H, dd), 7.11 (1H, d), 6.46-6.36 (3H, m), 3.99-3.82(5H, m), 3.75 (6H, s), 1.23 (3H, t).

Compound 201

¹H NMR (400 MHz, DMSO-d₆): 8.92 (1H, s), 8.54 (1H, s), 8.20 (1H, s),7.76 (1H, d), 6.99 (1H, dd), 6.81 (2H, dd), 6.64 (1H, d), 3.92 (6H, d),3.88-3.73 (5H, m), 1.24 (3H, t).

Compound 11

¹H NMR (400 MHz, DMSO-d₆): 8.98 (1H, s), 8.56 (1H, s), 8.22 (1H, s),7.78 (1H, d), 7.30 (1H, dd), 7.16 (1H, d), 6.43 (2H, d), 6.40 (1H, t),3.94 (3H, s), 3.74 (6H, s), 3.41 (3H, s).

Compound 202

¹H NMR (400 MHz, DMSO-d₆): 8.96 (1H, s), 8.56 (1H, s), 8.21 (1H, s),7.77 (1H, d), 7.26 (1H, dd), 7.13 (1H, d), 6.42 (3H, s), 3.93 (3H, s),3.82-3.70 (8H, m), 1.24-1.12 (1H, m), 0.53-0.43 (2H, m), 0.26-0.16 (2H,m).

Compound 12

¹H NMR (400 MHz, DMSO-d₆): 8.96 (1H, s), 8.56 (1H, s), 8.21 (1H, s),7.76 (1H, d), 7.26 (1H, dd), 7.08 (1H, d), 6.41 (3H, dd), 3.93 (3H, s),3.79 (2H, t), 3.75 (6H, s), 1.73-1.63 (2H, m), 0.96 (3H, t)

Compound 204

¹H NMR (400 MHz, DMSO-d₆): 9.00-8.94 (1H, m), 8.59-8.53 (1H, m),8.25-8.18 (1H, m), 7.77 (1H, d), 7.30 (1H, dd), 7.17 (1H, d), 6.44 (2H,d), 6.40 (1H, t), 4.03 (2H, t), 3.94 (3H, s), 3.74 (6H, s), 3.60 (2H,t), 3.29 (3H, s).

Compound 13

¹H NMR (400 MHz, DMSO-d₆): 8.97 (1H, s), 8.56 (1H, s), 8.21 (1H, s),7.77 (1H, d), 7.30 (1H, dd), 7.10 (1H, d), 6.41 (3H, s), 3.93 (3H, s),3.74 (6H, s), 3.69 (2H, d), 2.09-1.97 (1H, m), 0.98 (6H, d).

Compound 205

¹H NMR (400 MHz, DMSO-d₆): 9.02 (1H, s), 8.60-8.54 (1H, m), 8.22 (1H,s), 7.82 (1H, d), 7.36 (1H, dd), 7.24 (1H, d), 6.48 (2H, d), 6.40 (1H,t), 6.32 (1H, s), 5.25 (2H, s), 3.97-3.89 (3H, m), 3.78-3.69 (7H, m),3.29 (3H, s), 2.18 (3H, s).

Pharmacological Part Biological Assays A FGFR1 (Enzymatic Assay)

In a final reaction volume of 30 μL, FGFR1 (h) (25 ng/ml) was incubatedwith 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.1 mM Na₃VO₄, 0.01%Triton-X-100, 500 nM Btn-Flt3 and 5 μM ATP in the presence of compound(1% DMSO final). After incubation for 60 minutes at room temperature thereaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nMSA-XL-665 and 0.02% BSA which was present for 60 minutes at roomtemperature. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) signal (ex340 nm. Em 620 nm, em 655 nm) was measuredafterwards and results are expressed in RFU (Relative FluorescenceUnits). In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and plC₅₀ (−log IC₅₀) value.

FGFR2 (Enzymatic Assay)

In a final reaction volume of 30 μL, FGFR2 (h) (150 ng/ml) was incubatedwith 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.1 mM Na₃VO₄, 0.01%Triton-X-100, 500 nM Btn-Flt3 and 0.4 μM ATP in the presence of compound(1% DMSO final). After incubation for 60 minutes at room temperature thereaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nMSA-XL-665 and 0.02% BSA which was present for 60 minutes at roomtemperature. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) signal (ex340 nm. Em 620 nm, em 655 nm) was measuredafterwards and results are expressed in (Relative Fluorescence Units).In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and plC₅₀ (−log IC₅₀) value.

FGFR3 (Enzymatic Assay)

In a final reaction volume of 30 μL, FGFR3 (h) (40 ng/ml) was incubatedwith 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.1 mM Na₃VO₄, 0.01%Triton-X-100, 500 nM Btn-Flt3 and 25 μM ATP in the presence of compound(1% DMSO final). After incubation for 60 minutes at room temperature thereaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nMSA-XL-665 and 0.02% BSA which was present for 60 minutes at roomtemperature. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) signal (ex340 nm. Em 620 nm, em 655 nm) was measuredafterwards and results are expressed in RFU (Relative FluorescenceUnits). In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and plC₅₀ (−log IC₅₀) value.

FGFR4 (Enzymatic Assay)

In a final reaction volume of 30 μL, FGFR4 (h) (60 ng/ml) was incubatedwith 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.1 mM Na₃VO₄, 0.01%Triton-X-100, 500 nM Btn-Flt3 and 5 μM ATP in the presence of compound(1% DMSO final). After incubation for 60 minutes at room temperature thereaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nMSA-XL-665 and 0.02% BSA which was present for 60 minutes at roomtemperature. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) signal (ex340 nm. Em 620 nm, em 655 nm) was measuredafterwards and results are expressed in RFU (Relative FluorescenceUnits). In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and plC50 (−log IC₅₀) value.

KDR (VEGFR2) (Enzymatic Assay)

In a final reaction volume of 30 μL, KDR (h) (150 ng/ml) was incubatedwith 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.1 mM Na₃VO₄, 0.01%Triton-X-100, 500 nM Btn-Flt3 and 3 μM ATP in the presence of compound(1% DMSO final). After incubation for 120 minutes at room temperaturethe reaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nMSA-XL-665 and 0.02% BSA which was present for 60 minutes at roomtemperature. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) signal (ex340 nm. Em 620 nm, em 655 nm) was measuredafterwards and results are expressed in RFU (Relative FluorescenceUnits). In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and plC₅₀ (−log IC₅₀) value.

Ba/F3-FGFR1 (Minus IL3 or Plus IL3) (Cellular Proliferation Assay)

In a 384 well plate, 100 nl of compound dilution in DMSO was sprayedbefore adding 50 μl cell culture medium (phenol red free RPMI-1640, 10%FBS, 2 mM L-Glutamine and 50 μg/ml Gentamycin) containing 20000 cellsper well of Ba/F3-FGFR1-transfected cells. Cells were put in anincubator at 37° C. and 5% CO₂. After 24 hours, 10 μl of Alamar Bluesolution (0.5 mM K₃Fe(CN)₆, 0.5 mM K₄Fe(CN)₆, 0.15 mM Resazurin and 100mM Phosphate Buffer) was added to the wells, incubated for 4 hours at37° C. and 5% CO₂ before RFU's (Relative Fluorescence Units) (ex. 540nm., em. 590 nm.) were measured in a fluororescence plate reader.

In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and plC₅₀ (−log IC₅₀) value. As a counterscreenthe same experiment was performed in the presence of 10 ng/ml murineIL3.

Ba/F3-FGFR3 (Minus IL3 or Plus IL3) (Cellular Proliferation Assay)

In a 384 well plate, 100 nl of compound dilution in DMSO was sprayedbefore adding 50 μl cell culture medium (phenol red free RPMI-1640, 10%FBS, 2 mM L-Glutamine and 50 μg/ml Gentamycin) containing 20000 cellsper well of Ba/F3-FGFR3-transfected cells. Cells were put in anincubator at 37° C. and 5% CO₂. After 24 hours, 10 μl of Alamar Bluesolution (0.5 mM K₃Fe(CN)₆, 0.5 mM K₄Fe(CN)₆, 0.15 mM Resazurin and 100mM Phosphate Buffer) was added to the wells, incubated for 4 hours at37° C. and 5% CO₂ before RFU's (Relative Fluorescence Units) (ex. 540nm., em. 590 nm.) were measured in a fluororescence plate reader.

In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and plC₅₀ (−log IC₅₀) value. As a counterscreenthe same experiment was performed in the presence of 10 ng/ml murineIL3.

Ba/F3-KDR (Minus IL3 or Plus IL3) (Cellular Proliferation Assay)

In a 384 well plate, 100 nl of compound dilution in DMSO was sprayedbefore adding 50 μl cell culture medium (phenol red free RPMI-1640, 10%FBS, 2 mM L-Glutamine and 50 μg/ml Gentamycin) containing 20000 cellsper well of Ba/F3-KDR-transfected cells. Cells were put in an incubatorat 37° C. and 5% CO₂. After 24 hours, 10 μl of Alamar Blue solution (0.5mM K₃Fe(CN)₆, 0.5 mM K₄Fe(CN)₆, 0.15 mM Resazurin and 100 mM PhosphateBuffer) was added to the wells, incubated for 4 hours at 37° C. and 5%CO₂ before RFU's (Relative Fluorescence Units) (ex. 540 nm., em. 590nm.) were measured in a fluororescence plate reader.

In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and plC₅₀ (−log IC₅₀) value. As a counterscreenthe same experiment was performed in the presence of 10 ng/ml murineIL3.

Ba/F3-Flt3 (Minus IL3 or Plus IL3) (Cellular Proliferation Assay)

In a 384 well plate, 100 nl of compound dilution in DMSO was sprayedbefore adding 50 μl cell culture medium (phenol red free RPMI-1640, 10%FBS, 2 mM L-Glutamine and 50 μg/ml Gentamycin) containing 20000 cellsper well of Ba/F3-Flt3-transfected cells. Cells were put in an incubatorat 37° C. and 5% CO₂. After 24 hours, 10 μl of Alamar Blue solution (0.5mM K₃Fe(CN)₆, 0.5 mM K₄Fe(CN)₆, 0.15 mM Resazurin and 100 mM PhosphateBuffer) was added to the wells, incubated for 4 hours at 37° C. and 5%CO₂ before RFU's (Relative Fluorescence Units) (ex. 540 nm., em. 590nm.) were measured in a fluororescence plate reader.

In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and plC₅₀ (−log IC₅₀) value. As a counterscreenthe same experiment was performed in the presence of 10 ng/ml murineIL3.

Data for the compounds of the invention in the above assays are providedin Table A2.

TABLE A2 BAF3- BAF3- BAF3- BAF3- BAF3- BAF3- BAF3- FGFR1 FGFR1 FGFR3FGFR3 KDR KDR FLT3 BAF3_FLT3 VEGFR2 (MIN (PLUS (MIN (PLUS (MIN (PLUS(MIN (PLUS Co. FGFR1 FGFR2 FGFR3 FGFR4 (KDR) IL3) IL3) IL3) IL3) IL3)IL3) IL3) IL3) No. pIC₅₀ pIC₅₀ pIC₅₀ pIC₅₀ pIC₅₀ pIC₅₀ pIC₅₀ pIC₅₀ pIC₅₀pIC₅₀ pIC₅₀ pIC₅₀ pIC₅₀ 200 8.53 8.11 8.73 7.92 7.05 6.41 <5 6.61 <55.79 <5 5.2 <5 11 8.36 7.91 8.66 7.76 7.43 6.3 <5 6.43 <5 6.06 <5 5.71<5 202 8.11 7.71 ~8.33 7.61 6.58 5.95 <5 6.1 <5 5.14 <5 <5 <5 8.18 7.98.45 7.6 6.72 6.15 <5 5.93 <5 5.18 <5 <5 <5 17 7.93 7.48 8.15 7.13 6.395.95 <5 5.67 <5 <5 <5 <5 <5 203 7.26 7.19 7.75 6.73 6.17 5.49 <5 5.54 <5<5 <5 <5 <5 204 8.27 7.93 8.47 7.55 6.79 6.53 <5 6.64 <5 5.35 <5 <5 <5205 8.85 8.46 9 8.55 7.07 6.42 <5 7.09 <5 5.52 <5 5.24 <5 206 8.15 7.918.52 7.46 6.67 5.79 <5 6.15 <5 <5 <5 <5 <5 207 8.86 8.32 8.64 7.45 7.185.59 <5 ~5.56 ~5.24 <5 <5 <5 <5 56 8.35 8.19 8.68 7.55 6.92 6.12 <5 5.72<5 <5 <5 <5 <5 8.37 8.09 8.55 7.57 6.97 6.28 <5 5.9 <5 5.06 <5 <5 <5 2087.35 7.21 7.26 6.8 5.82 5.73 <5 5.66 <5 <5 <5 <5 <5 209 5.92 ~6.07 6.225.29 6.18 <5 <5 <5 <5 <5 <5 <5 <5 210 8.37 8.03 8.45 7.75 6.75 6.7 <56.53 <5 5.26 <5 <5 <5 211 8.29 7.88 8.13 7.39 6.7 6.44 <5 6.01 <5 5.26<5 <5 <5 1 8.59 8.5 9.05 8.25 7.07 7.04 <5 6.89 <5 6.03 <5 <5 <5 8.648.41 8.95 8.27 7.1 6.56 <5 6.86 <5 5.6 <5 5.09 <5 212 8.43 8.15 8.867.83 6.92 6.36 <5 5.98 <5 ~5.02 <5 <5 <5 213 8.33 8.09 8.55 7.74 6.656.45 <5 6.06 <5 <5 <5 <5 <5 214 7.16 7 7.39 6.33 5.74 <5 <5 <5 <5 <5 <5<5 <5 216 8.86 8.28 8.58 7.66 6.79 5.69 <5 6.05 ~5.02 ~5.06 ~5.09 ~5.26~5.2 22 5.99 6.07 6.12 <5 5.92 <5 <5 <5 <5 <5 <5 <5 <5 60 8.99 8.42 9.017.84 7.37 5.8 ~5.19 6.15 ~5.27 ~5.27 ~5.26 ~5.27 ~5.08 122 8.77 8.49 9.18.21 7.12 6.36 <5 6.87 <5 5.47 <5 <5 <5 58 6.17 6.39 6.78 <6 <6 <5 <5~5.09 <5 <5 <5 <5 <5 3 8.71 8.63 9.03 8.29 7.75 7.24 <5 7.1 <5 5.91 <55.22 <5 8.77 8.49 8.97 8.25 7.39 218 8.42 ~8.05 8.29 7.63 6.62 6.71 <56.61 <5 <5 <5 <5 <5 219 6.95 6.92 7.23 6.12 <6 5.05 <5 5.23 <5 <5 <5 <5<5 220 7.27 7.01 7.53 6.59 6.48 5.44 <5 5.34 <5 <5 <5 <5 <5 221 6.636.62 7.08 <6 6.97 <5 <5 ~5 <5 <5 <5 <5 <5 223 8.74 8.44 9.04 8.37 6.956.73 <5 7 <5 5.3 <5 <5 <5 224 7.84 7.83 8.2 7.51 7.19 5.64 <5 5.6 <55.37 <5 5.23 <5 62 8.9 8.45 9.06 7.92 7.55 5.88 ~5.25 6.06 ~5.25 ~5.27~5.27 ~5.27 ~5.26 23 8.73 8.54 9.15 8.35 6.91 7.02 <5 6.74 <5 5.28 <5 <5<5 226 8.16 8.07 8.69 7.52 6.46 6 <5 6.11 <5 <5 <5 <5 <5 8 8.84 8.488.61 7.98 7.15 5.96 <5 7.12 <5 <5 <5 <5 <5 8.84 8.82 8.49 7.95 7.55 6.07<5 7.07 <5 <5 <5 <5 <5 84 8.76 8.55 8.75 8.1 7.43 6.57 <5 6.92 <5 5.63<5 <5 <5 8.67 8.8 8.73 8.03 7.56 7.29 <5 7.16 <5 5.96 <5 <5 <5 8.76 8.618.71 8.12 7.44 6.75 <5 6.82 <5 5.73 <5 <5 <5 8.66 8.71 8.73 7.95 7.436.47 <5 7.06 <5 5.75 <5 <5 <5 8.74 8.48 8.62 7.8 7.3 6.58 <5 7.15 <55.57 <5 <5 <5 8.92 8.47 8.69 7.88 7.08 6.1 <5 7.03 <5 5 <5 <5 <5 8.968.56 8.74 8.06 7.46 6.08 <5 7.07 <5 <5 <5 <5 <5 8.78 8.4 8.66 7.97 7.525.94 <5 7.11 <5 <5 <5 <5 <5 8.81 8.64 8.64 7.98 7.27 6.87 <5 7.29 <55.73 <5 <5 <5 227 8.27 8.03 8.6 7.8 6.78 5.76 <5 6.57 <5 <5 <5 <5 <5 658.51 8.19 8.35 7.49 6.46 6 <5 6.56 <5 <5 <5 <5 <5 229 8.53 8.14 8.957.64 6.68 5.75 <5 6.39 <5 <5 <5 <5 <5 73 8.73 8.53 8.64 7.46 7.31 6.09~5.07 6 ~5.25 ~5.23 ~5.24 ~5.25 <5 231 8.16 8.29 8.45 7.38 7 5.71 <56.23 <5 ~5.08 <5 <5 <5 59 7.76 7.95 8.07 6.99 6.59 6.34 <5 6.55 <5 <5 <5<5 <5 52 8.04 7.82 8.21 7.28 6.91 5.7 <5 6.17 <5 <5 <5 <5 <5 232 <6 <66.17 <6 <6 <5 <5 <5 <5 <5 <5 <5 <5 64 7.67 7.39 7.29 7.09 <6 6.17 <55.75 <5 <5 <5 <6 <5 233 8.76 8.57 8.93 8.13 7.27 6.66 <5 6.97 <5 5.59 <5<5 <5 19 8.09 8.01 8.17 6.93 6.86 5.2 <5 ~5.68 ~5.23 <5 <5 ~5.18 <5 1308.32 8.19 8.54 7.37 7.69 6.16 ~5.25 6.06 ~5.33 ~5.62 ~5.3 ~5.28 ~5.26235 8.78 8.53 8.68 7.42 7.26 5.72 <5 6.15 <5 <5 <5 <5 <5 69 7.72 7.337.93 6.95 6.16 5.99 <5 6.29 <5 <5 <5 <5 <5 7.72 7.43 7.77 7.02 6.05 5.55<5 6.1 <5 <5 <5 <5 <5 237 6.84 6.99 7.35 6.5 6.14 ~5.16 <5 ~5.17 <5 <5<5 <5 <5 238 9.01 8.57 8.88 7.76 7.54 6.2 <5 6.89 <5 5.32 <5 <5 <5 666.54 6.96 7.22 6.18 <6 <5 <5 ~5.04 <5 <5 <5 <5 <5 2 ~8.64 8.48 9.02 8.036.86 6.51 <5 7.04 <5 5.41 <5 <5 <5 8.56 8.33 8.79 7.97 7.34 7.1 <5 7.05<5 5.49 <5 <5 <5 113 8.35 8.18 8.71 7.8 6.69 6.71 <5 6.95 <5 5.45 <5 <5<5 68 5.86 5.99 ~6.06 <5 5.91 <5 <5 ~5.11 ~5.15 <5 <5 5.21 <5 239 ~8.668.5 8.76 7.33 7.14 5.94 <5 5.91 ~5.28 5.25 ~5.21 ~5.26 ~5.25 240 8.78.26 8.75 7.17 7.01 6.08 <5 5.71 ~5.26 ~5.14 ~5.26 ~5.26 <5 241 9.128.86 9.05 8.51 7.74 8.02 <5 8.03 ~5.06 6.69 <5 ~5.09 <5 9.43 8.78 8.738.59 7.61 7.97 <5 8.01 ~5.08 6.65 <5 ~5.14 <5 55 8.72 8.52 8.75 7.247.12 6.1 ~5.16 5.95 ~5.27 ~5.24 ~5.25 ~5.26 ~5.2 242 8.62 8.61 8.9 8.017.44 6.96 <5 7 <5 5.77 <5 <5 <5 243 8.66 8.36 8.89 7.61 7.04 6.01 <56.01 ~5.25 ~5.02 ~5.2 ~5.21 ~5.19 244 8.27 8.29 8.49 7 6.76 5.84 <5 5.77~5.25 ~5.05 ~5.08 ~5.24 <5 245 8.2 8.02 8.37 6.71 6.87 6.91 <5 6.82 <55.94 <5 <5 <5 246 8.22 8.09 8.65 7.28 6.47 5.69 <5 6.11 <5 <5 <5 <5 <524 7.88 7.94 8.52 7.32 6.82 5.97 <5 5.86 <5 ~5.01 <5 <5 <5 249 8.45 8.318.65 7.09 7.36 6.55 <5 6.56 <5 5.64 <5 <5 <5 250 8.35 8.08 8.59 7.376.49 5.73 <5 6.09 <5 <5 <5 <5 <5 251 7.73 7.73 7.93 6.12 6.34 5.31 <5~5.29 ~5.26 ~5.12 ~5.23 ~5.26 ~5.37 21 8.75 8.48 9.07 8.07 6.79 6.75 <56.8 <5 5.56 <5 <5 <5 72 8.8 ~8.5 8.91 7.33 7.22 6.1 ~5.05 6.03 ~5.29~5.28 ~5.26 ~5.27 ~5.19 253 8.54 8.33 8.74 7.6 6.78 5.92 <5 6.07 <5 <5<5 <5 <5 254 8.41 8.19 8.52 7.52 6.35 6.13 <5 6.11 <5 <5 <5 <5 <5 747.78 7.9 8 7.07 <6 6.14 <5 6.42 <5 <5 <5 <5 <5 70a 8.57 8.52 8.23 7.587.23 6.91 <5 7.13 <5 5.77 <5 <5 <5 256 9.21 8.54 8.88 8.31 7.28 7 <56.89 <5 <5 <5 <5 <5 26 8.76 8.47 8.9 8.11 7.14 6.85 <5 6.76 <5 5.64 <55.22 <5 257 7.96 7.58 7.9 7.59 6.49 6.46 <5 6.57 <5 <5 <5 <5 <5 75 8.738.42 8.87 8.12 7.15 7.05 <5 6.9 <5 5.7 <5 <5 <5 8.5 8.42 8.79 8.1 6.776.69 <5 7.11 <5 5.5 <5 <5 <5 7 8.3 8.17 8.57 7.92 6.66 6.36 <5 6.58 <55.26 <5 <5 <5 259 8.81 8.63 9.1 8.4 7.28 7.24 <5 7.17 <5 5.45 <5 <5 <5260 8.79 8.51 8.9 8.18 7.47 7.2 <5 6.88 <5 5.58 <5 <5 <5 27 6.13 6.566.3 <6 6.4 5.67 <5 <5 <5 6.17 <5 5.32 <5 78 8.13 7.93 8.4 7.42 6.77 6.19<5 6.12 <5 5.24 <5 <5 <5 8.22 8.11 8.36 7.45 6.96 6.63 <5 6.46 <5 ~5.68<5 <5 <5 8.1 8.03 8.43 7.52 6.68 6.26 <5 6.26 <5 5.38 <5 <5 <5 261 8.718.5 8.39 8.14 7.38 5.96 <5 7.07 <5 <5 <5 <5 <5 262 9.29 9.35 8.91 7.867.74 <5 7.87 <5 6.75 <5 <5 <5 25 9.11 8.64 8.43 7.92 7.04 7.36 <5 7.22<5 5.73 <5 <5 <5 8.78 8.61 8.52 7.78 7.11 7.35 <5 7.36 <5 5.86 <5 <5 <5263 8.75 8.52 8.75 8.14 7.39 6.72 <5 6.75 <5 5.54 <5 <5 <5 264 8.97 8.758.45 8.09 7.78 7.47 <5 7.58 <5 6.12 <5 <5 <5 265 8.79 8.59 8.44 8.047.05 6.51 <5 6.65 <5 5.24 <5 <5 <5 266 8.76 8.62 8.33 7.97 7.37 5.79 <56.9 <5 <5 <5 <5 <5 76 8.46 8.19 8.43 7.65 7.05 7.18 5 6.92 <5 6.08 5.025.09 <5 267 7.83 7.7 8 7.43 6.2 5.69 <5 5.76 <5 <5 <5 <5 <5 268 9.438.74 9.14 9.05¶ 7.96 7.74 <5 8.09 <5 6.69 <5 <5 <5 9.25 8.75 9.41 8.787.96 7.86 <5 7.89 <5 6.69 <5 <5 <5 269 6.28 6.44 6.51 <6 <6 <5 <5 <5 <5<5 <5 <5 <5 271 8.14 7.87 8.58 7.61 6.75 6.14 <5 6.19 <5 ~5.06 <5 <5 <5272 9.02 8.75 8.82 8.37 7.6 7.36 <5 7.77 <5 6.24 <5 ~5.18 <5 273 7.117.09 6.71 <6 6.29 5.73 <5 5.68 <5 5.29 <5 <5 <5 274 6.1 6.27 6.65 <6 ~6<5 <5 <5 <5 <5 <5 <5 <5 121 8.12 7.86 8.2 7.02 6.63 6.14 <5 ~6.06 <55.55 <5 5.35 <5 4 9.01 8.35 8.42 8.21 7.32 7.23 <5 7.31 <5 5.48 <5 ~5.05<5 8.77 8.81 8.49 8.18 7.43 7.08 <5 7.82 <5 6.05 <5 <5 <5 8.73 8.76 8.58.23 7.46 7.72 <5 7.86 <5 6.11 <5 5 <5 8.96 8.73 8.57 8.31 7.46 7.6 <58.05 <5 5.96 <5 <5 <5 8.92 8.67 8.44 8.25 7.33 8.07 <5 8.07 <5 6.48 <5<5 <5 9.09 8.58 8.6 8.29 7.45 7.61 <5 8.13 <5 6.04 <5 <5 <5 9.01 8.648.56 8.33 7.5 7.61 <5 7.98 ~5.12 6 <5 <5 <5 8.99 8.56 8.6 8.18 7.58 7.89<5 7.8 <5 6.24 <5 <5 <5 276 8.6 8.46 8.93 8.17 7.23 6.99 <5 ~7.17 <55.65 <5 <5 <5 28 8.62 8.47 8.83 8.09 7.35 7.15 <5 7.14 <5 5.58 <5 <5 <537 8.04 7.99 8.62 7.59 7.14 5.88 ~5.07 5.82 <5 ~5.1 <5 <5 <5 278 8.468.34 8.44 7.66 7.18 5.92 <5 7.09 <5 <5 <5 <5 <5 279 8.43 8.3 8.4 7.57.16 5.76 <5 7.04 <5 <5 <5 <5 <5 280 8.66 8.39 8.44 7.87 7.31 6.94 <57.49 <5 5.34 <5 <5 <5 281 8.41 8.36 8.18 7.59 7.14 7.33 <5 7.1 <5 5.94<5 ~5.15 <5 283 6.39 6.65 6.68 <6 6.31 5.23 <5 ~5.21 <5 ~5.18 <5 <5 <579/79a 8.62 8.55 8.58 7.82 6.91 7.29 <5 7.58 <5 5.8 <5 <5 <5 602 8.068.14 8.13 7.51 7 6.57 <5 6.6 <5 5.28 <5 <5 <5 81 8.21 8.16 8.84 7.487.02 6.61 <5 6.43 <5 5.24 <5 <5 <5 80 8.33 8.13 8.72 7.59 6.86 6.69 <56.59 <5 5.31 <5 <5 <5 284 9.07 8.8 8.68 8.4 7.39 7.69 <5 7.82 ~5.08 5.72<5 <5 <5 9.26 8.8 8.8 8.33 7.73 7.56 <5 7.77 ~5.01 6.17 <5 ~5.1 <5 2868.75 8.49 8.56 8.14 7.68 7.24 <5 7.32 5.03 5.86 <5 <5 <5 287 8.33 8.38.63 7.8 7.69 6.38 <5 6.75 <5 <5 <5 <5 <5 29 ~6.1 6.1 6.32 <6 ~5.96 <5<5 5.24 5.28 <5 <5 5.22 <5 288 7.65 ~7.77 7.73 7.04 6.76 5.15 <5 6.58 <5<5 <5 <5 <5 291 8.87 8.71 8.77 8.39 7.97 7.72 <5 7.79 <5 6.65 <5 <5 <5293 7.01 6.99 7.49 6.49 6.23 <5 <5 <5 <5 <5 <5 <5 <5 294 8.67 8.4 8.647.69 7.28 5.78 <5 6.9 <5 <5 <5 <5 <5 8.62 8.6 8.52 7.75 7.07 6.24 <56.94 <5 5.4 <5 <5 <5 16 7.81 7.78 8.34 7.39 6.53 6.17 <5 5.78 <5 <5 <5<5 <5 20 8.25 8.31 8.84 7.85 7.16 6.07 <5 6.06 <5 ~5 <5 <5 <5 295 8.868.61 8.75 8.14 7.6 7.97 <5 7.79 <5 6.32 <5 <5 <5 296 8.61 8.53 8.46 86.87 7.47 <5 7.65 <5 5.96 <5 <5 <5 54 6.16 6.07 6.11 <6 ~6.04 <5 <5 <5<5 <5 <5 <5 <5 297 8.19 8.35 8.5 7.66 7.24 5.35 <5 5.56 <5 <5 <5 <5 <5298 8.42 8.45 8.18 7.65 6.72 6.71 <5 6.37 <5 5.21 <5 <5 <5 299 8.06 8.238.48 7.72 7.31 6.81 <5 6.88 <5 5.74 <5 <5 <5 49 8.93 8.34 9.19 8.33 7.537.13 <5 7.06 <5 5.58 <5 5.43 <5 93 8.95 8.66 8.86 8.23 7.65 6.98 <5 6.97<5 5.81 <5 <5 <5 8.85 8.46 8.64 8.04 7.58 6.8 <5 6.42 <5 5.47 <5 ~5.01<5 302 8.97 8.72 8.68 8.28 7.59 7.93 <5 7.91 <5 6.64 <5 <5 <5 303 8.438.48 8.33 7.66 7.92 6.73 <5 6.7 ~5.01 6.43 <5 <5 <5 304 8.15 7.82 8.137.33 7.13 5.74 <5 7.08 <5 <5 <5 <5 <5 305 6.38 <5 6.67 <5 5.07 <5 <5 <561 5.83 ~5.19 ~5.67 ~5.28 ~5.15 ~5.25 5.12 ~5.12 306 5.74 <5 5.64 <5 <5<5 <5 <5 307 5.74 <5 5.63 <5 <5 <5 <5 <5 308 6.1 <5 6.87 <5 <5 <5 6.84<5 311 6.38 <5 6.45 <5 5.38 <5 <5 <5 312 5.76 <5 5.86 <5 <5 <5 <5 <5 3138.67 8.53 9.01 8.27 7.08 6.98 <5 7.1 <5 5.65 <5 <5 <5 6.56 <5 7.09 <55.56 <5 5.09 <5 314 5.92 <5 6.05 <5 <5 <5 <5 <5 30 6.71 <5 6.32 <5 5.42<5 5.21 <5 38 8.69 8.21 8.55 7.78 7.06 5.93 <5 6.5 <5 5.14 <5 <5 <5 3156.6 <5 6.07 <5 5.34 <5 <5 <5 48 7.43 <5 7.53 <5 6.45 <5 <5 <5 316 7.44<5 7.48 <5 6.35 <5 <5 <5 321 8.85 8.7 8.68 7.99 7.72 6.6 <5 6.92 <5 5.81<5 <5 <5 57 7.97 7.84 8.42 7.35 6.54 5.92 <5 6.31 <5 <5 <5 <5 <5 3236.58 6.78 6.84 <6 <6 <5 <5 <5 <5 <5 <5 <5 <5 85 7.78 7.84 8.18 7.04 6.595.56 <5 6.14 <5 <5 <5 <5 <5 324 8.81 8.65 8.5 7.9 7 7.12 <5 7.46 <5 5.63<5 <5 <5 325 7.57 7.7 7.3 6.51 6.12 5.79 <5 6.26 <5 <5 <5 <5 <5 86 8.398.13 8.58 7.85 7.1 <5 <5 <5 <5 <5 <5 <5 <5 326 8.04 8.05 8.48 7.46 6.796.18 <5 6.39 <5 5.12 <5 <5 <5 83 8.47 8.45 7.97 7.35 6.98 6.68 <5 6.86<5 5.63 <5 <5 <5 327 6.88 7.11 7.52 6.51 6.16 <5 <5 5 <5 <5 <5 <5 <5 3289.14 8.71 8.78 8.29 7.7 6.94 <5 7.13 5.11 5.76 <5 ~5.12 <5 330 8.85 8.658.51 7.75 7.47 6.49 <5 6.7 ~5.08 ~5.56 ~5.08 ~5.19 <5 332 8.82 8.67 8.527.85 7.33 7.27 <5 7.57 <5 6.04 <5 <5 <5 333 8.47 8.39 8.42 7.86 7.155.68 <5 6.13 <5 <5 <5 <5 <5 334 7.37 7.2 7.29 6.61 <6 <5 <5 <5 <5 <5 <5<5 <5 335 9.06 8.84 9.23 8.68 7.67 7.13 <5 7.6 <5 6.09 <5 <5 <5 336 8.518.5 8.7 7.88 6.86 6.36 <5 6.85 <5 5.37 <5 <5 <5 338 9.21 ~8.93 8.89 8.167.43 6.52 <5 7.12 <5 5.53 <5 <5 <5 339 8.24 8.19 8.04 7.16 7.17 5.92 <56.11 <5 <5 <5 <5 <5 32 6.56 6.4 6.61 <6 <6 <5 <5 5.37 <5 <5 <5 <5 <5 1317.94 8.01 8.47 7.35 6.71 6.1 <5 6.31 <5 5.07 <5 <5 <5 340 8.05 8.05 8.397.3 6.6 6.54 <5 7.26 <5 5.22 <5 <5 <5 342 8.91 8.6 8.43 7.93 7.26 7.31<5 7.59 <5 5.83 <5 <5 <5 343 8.55 8.47 8.42 7.6 7.02 6.52 <5 6.56 <55.28 <5 <5 <5 344 8.68 8.47 8.18 7.35 7.24 6.9 <5 7.22 <5 5.95 <5 6.12<5 31 9.01 8.51 9.21 8.42 7.24 6.85 <5 7.41 <5 5.71 <5 5.32 <5 8.86 8.619.06 8.51 7.34 6.96 <5 7.29 <5 5.87 <5 5.53 <5 345 8.38 8.41 8.73 7.637.06 5.82 <5 6.32 ~5.02 ~5.01 <5 ~5.01 <5 346 ~6.64 6.55 6.45 6.59 <65.17 <5 5.68 <5 <5 <5 <5 <5 347 8.85 8.67 8.64 8.24 7.2 7.46 <5 7.99 <56.09 <5 ~5.12 <5 348 8.07 7.91 8.04 7.37 6.61 6.21 <5 6.61 <5 5.21 <5 <5<5 351 8.34 8.29 7.8 6.98 7.04 5.93 <5 6.59 <5 ~5.38 <5 <5 <5 89 8.438.35 8.52 7.6 7.01 6.33 <5 6.82 <5 5.31 <5 <5 <5 352 8.98 8.54 8.64 8.297.37 7.5 <5 7.89 <5 5.89 <5 <5 <5 87 9.01 8.73 8.88 8.46 7.62 7.51 <57.89 <5 6.39 <5 5.07 <5 353 7.68 7.73 8.07 7.06 6.33 5.64 <5 6.2 <5 <5<5 <5 <5 354 8.51 8.08 8.43 7.7 6.57 6.2 <5.52 6.68 <5.52 <5.52 <5.52<5.52 <5.52 355 7.49 7.21 7.19 6.21 6.23 5.19 <5 5.55 <5 <5 <5 <5 <5 356~8.07 8.06 8.23 7.49 6.83 6.2 <5 6.56 <5 5.22 <5 <5 <5 53 6.45 6.47 6.38~6.15 6.34 <5 <5 <5 <5 <5 <5 <5 <5 91 7.91 7.71 8.25 7.47 6.59 <5 <5~5.27 <5 <5 <5 <5 <5 18 7.3 6.9 6.98 6.58 6.64 5.44 <5 6.07 <5 <5 <5 <5<5 357 8.74 8.37 8.38 7.7 7.11 6.91 <5 7.38 <5 5.69 <5 <5 <5 358 6.837.01 6.97 6.64 <6 <5 <5 5.12 <5 <5 <5 <5 <5 359 7.65 7.57 7.66 7.12 6.145.69 <5 6.15 <5 <5 <5 <5 <5 360 7.87 7.67 7.89 6.9 6.16 5.5 <5 5.98 <5<5 <5 <5 <5 361 7.47 7.42 7.27 6.15 6.1 5.67 <5 6.05 <5 5.17 <5 5.25 <5362 8.62 8.26 8.32 7.78 7.09 6.6 <5 7.17 <5 5.54 <5 <5 <5 363 8.92 8.718.95 8.36 7.51 6.52 <5 6.7 <5 5.28 <5 <5 <5 9 8.75 8.84 8.35 7.33 5.8 <56.57 <5 5.07 <5 <5 <5 364 8.41 8.19 8.23 7.59 7.69 5.94 <5 6.45 <5 5.8<5 <5 <5 365 8.64 8.41 8.57 7.97 7.52 6.29 <5 6.94 <5 5.74 <5 <5 <5 3668.94 8.6 8.62 8.18 7.31 7.23 <5 7.92 <5 5.95 <5 <5 <5 367 9.26 8.86 8.948.54 7.47 7.17 <5 7.63 <5 6.02 <5 <5 <5 300 8.15 7.99 8.38 7.9 7.01 >8<5 >8 <5 5.29 <5 5.09 <5 8.14 8.46 8.41 7.87 7.2 7.9 5.28 8.18 ~5.125.56 5.1 5.33 5.17 8.35 8.41 8.59 7.84 7.02 6.92 <5 7.81 <5 5.21 <5 5.11<5 368 ~8.96 8.7 8.81 8.09 7.23 5.93 <5 6.41 <5 5.14 <5 <5 <5 369 7.767.93 7.5 6.73 7.63 5.2 <5 5.57 <5 <5 <5 <5 <5 370 8.68 8.57 8.61 8 6.865.95 <5 6.51 <5 <5 <5 <5 <5 371 8.8 8.68 8.42 8.17 7.24 6.04 ~5.03 6.64~5.17 5.58 5.13 ~5.22 ~5.13 92 9.09 8.57 8.99 8.74 7.64 6.65 <5 7.72 <55.79 <5 <5 <5 8.96 8.6 8.97 8.73 7.81 7.39 <5 7.55 <5 6.16 <5 <5 <5 9.048.45 8.99 8.58 7.65 7.74 <5 7.83 <5 6.23 <5 <5 <5 373 7.96 7.97 7.977.26 6.62 5.63 <5 6.1 <5 <5 <5 <5 <5 374 6.55 <5 6.96 <5 5.15 <5 <5 <5375 8.63 8.59 9.06 8.19 6.99 6.88 <5 7.36 <5 5.3 <5 <5 <5 7.13 <5 7.17<5 5.84 <5 <5 <5 376 6.92 <5 7.32 <5 5.91 <5 5.04 <5 377 6.26 <5 6.75 <55.41 <5 <5 <5 378 8.46 8.41 8.19 7.66 6.86 7.18 <5 7.37 <5 5.43 <5 <5 <57.43 <5 7.57 <5 5.83 <5 <5 <5 379 8.23 8.52 8.25 7.51 7.22 6.13 <5 6.49~5.19 5.14 <5 <5 <5 6.48 <5 6.59 5.1 ~5.49 ~5.08 ~5.16 <5 380 6.69 <56.85 <5 5.32 <5 <5 <5 381 6.81 <5 7.14 <5 5.59 <5 <5 <5 382 8.96 8.698.67 8.05 6.93 7.29 <5 7.63 ~5.05 5.56 <5 <5 <5 7.5 <5 7.69 <5 5.79 <5<5 <5 132 8.12 8.54 8.43 7.73 7.46 6.26 <5 6.75 <5 5.4 <5 <5 <5 6.84 <56.65 <5 5.68 <5 <5 <5 108 9 8.86 8.74 8.19 7.5 7.67 <5 7.68 <5 6.15 <55.12 <5 7.45 <5 7.59 <5 5.98 <5 <5 <5 384 7.21 <5 7.51 <5 5.51 <5 <5 <5385 5.49 <5 5.81 <5 <5 <5 <5 <5 39 6.56 <5 6.8 <5 5.23 <5 <5 <5 40 6.25<5 6.47 <5 5.19 <5 <5 <5 133 8.52 8.28 8.73 7.94 7.08 6.82 <5 7.06 <55.62 <5 <5 <5 6.74 <5 7.12 <5 5.64 <5 <5 <5 386 ~5.56 <5 5.79 ~5.11 <55.05 <5 <5 387 5.25 <5 5.57 <5 <5 <5 <5 <5 389 6.67 <5 6.98 <5 5.23 <5<5 <5 390 7.17 <5 7.25 <5 5.62 <5 <5 <5 391 5.8 <5 6.13 <5 <5 <5 <5 <5392 7.91 7.77 8.19 7.14 6.9 5.95 <5 6.05 <5 5.34 <5 5.37 <5 395 9.358.81 8.87 8.72 8.08 7.78 <5 7.88 <5 6.75 <5 <5 <5 94 8.76 8.29 9.05 8.27.1 6.41 <5 6.74 <5 5.31 <5 <5 <5 8.47 8.47 8.85 8.19 7.07 6.9 <5 7.1 <55.62 <5 <5 <5 396 8.66 8.45 8.23 8.05 7.59 7.78 <5 8.02 ~5.16 6.62 <55.08 <5 397 8.43 8.36 8.96 7.98 6.87 6.75 <5 ~7.07 <5 5.26 <5 <5 <5 3988.85 8.59 8.67 8 7.75 6.44 <5 6.54 ~5.25 5.95 <5 ~5.16 <5 399 8.58 8.379.05 8.24 7.08 6.59 <5.52 6.87 <5 5.65 <5 5.1 <5 400 8.55 8.46 9.01 8.157.14 6.55 <5 6.5 <5 5.67 <5 5.1 <5 401 7.75 7.78 8.31 7.14 6.76 5.75 <55.93 <5 5.33 <5 <5 <5 405 7.2 6.89 7.08 6.59 <6 5.62 <5 5.79 <5 <5 <5 <5<5 407 7.21 6.84 7.25 6.35 6.11 <5 <5 ~5.08 <5 <5 <5 <5 <5 408 6.41 6.746.49 <6 ~6 <6 <5 6.38 <5 <5 <5 <5 <5 409 8.84 8.55 8.58 8.11 6.57 6.82<5 6.78 <5 5.47 <5 <5 <5 411 6.62 6.75 6.75 6 6.13 <5 <5 <5 <5 <5 <5 <5<5 412 8.14 8.36 8.1 7.42 6.93 6.35 <5 6.03 <5 5.31 <5 <5 <5 413 8.748.5 8.37 8.17 7.76 7.79 <5 7.94 5.09 6.4 <5 5.11 <5 414 8.54 8.43 8.277.64 7.17 6.65 <5 6.57 ~5.15 5.89 <5 ~5.98 <5 422 8.72 8.42 8.74 8.127.49 6.67 <5 7.29 <5 5.84 <5 <5 <5 423 8.73 8.46 8.81 8.18 7.42 7.4 <57.65 <5 6.07 <5 ~5.07 <5 426 6.94 6.8 6.69 <6 <6 5.43 <5 5.59 <5 <5 <5~5.05 <5 428 8.52 8.46 8.38 7.17 7.73 5.99 <5 5.8 <5 5.25 <5 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8.54 8.34 8.28 8.1 7.21 7.1 <5 7.22 <55.74 <5 <5 <5 456 8.74 8.47 8.5 8.05 7.13 6.44 <5 6.6 ~5.22 5.69 <5 <5<5 96 7.6 7.7 7.51 6.74 6.32 5.77 <5 5.9 ~5.21 ~5.06 <5 ~5 <5 457 9.088.58 8.85 8.07 7.3 6.19 <5 6.31 ~5.25 5.46 <5 ~5.11 ~5.05 458 8.44 8.318.55 7.89 6.97 6.79 <5 6.81 <5 5.28 <5 <5 <5 44/44a 8.1 7.98 7.84 7.516.51 6.06 <5 6.09 <5 5.04 <5 <5 <5 459 8.24 8.06 8.18 7.54 6.76 6.27 <56.84 <5 5.15 <5 <5 <5 460 7.76 8.04 8.17 6.94 7.05 6.7 <5 ~6.69 <5 5.53<5 <5 <5 463 8.54 7.65 7.42 <5 6.04 <5 <5 <5 464 8.58 8.65 8.57 8.4 7.886.86 <5 7.34 <5 5.71 <5 <5 <5 465 8.31 8.36 8.38 7.4 7.06 6.34 <5 6.73~5.15 5.35 <5 <5 <5 467 9.05 8.69 8.77 8.33 7.43 7.76 <5 7.95 <5 5.77 <5<5 <5 468 8.02 7.71 7.72 7.16 6.61 5.52 <5 5.61 <5 ~5.04 <5 <5 <5 4699.23 8.76 8.77 8.52 7.4 8.12 <5 8.08 <5 5.8 <5 <5 <5 470 8.75 8.56 8.557.83 7.1 6.6 <5 7.03 <5 5.38 <5 <5 <5 472 8.69 8.61 8.63 8.08 7.58 7.32<5 7.62 <5 5.57 <5 <5 <5 474 8.39 8.48 8.37 7.75 7.9 5.8 ~5.56 6.04 ~5.5~5.62 ~5.29 ~5.37 ~5.38 135 9.11 8.75 8.86 8.47 7.74 7.79 <5 7.83 ~5.115.82 <5 <5 <5 475 ~7.88 7.83 8.35 7.24 6.85 6.08 <5 6.06 <5 5.09 <5 <5<5 476 8.32 8.6 9.15 8.37 7.57 6.85 <5 7.02 <5 5.46 <5 5.53 <5 477 8.067.96 8.39 7.46 6.74 5.92 <5 5.98 <5 <5 <5 <5 <5 478 7.91 7.97 8.06 7.017.02 5.44 <5 5.7 <5 5.04 <5 <5 <5 136 8.82 8.66 8.64 8.36 7.63 8.02 <58.06 ~5.11 5.88 <5 ~5.06 <5 480 8.9 8.64 8.68 8 7.57 6.7 ~5.24 6.78~5.36 5.89 ~5.1 ~5.3 ~5.25 97 8.38 8.51 8.94 7.86 6.95 6.96 <5 7 <5 5.62<5 5.06 <5 8.13 8.19 8.75 7.9 6.94 6.38 <5 6.8 <5 5.12 <5 <5 <5 98 8.888.56 9.03 8.32 7.21 7.01 <5 7.25 <5 5.28 <5 <5 <5 8.64 8.62 8.96 8.246.79 7.13 <5 7.59 <5 5.82 <5 <5 <5 481 8.64 8.49 9.07 8.42 6.92 6.89 <57.3 <5 5.27 <5 <5 <5 482 8.95 8.6 8.79 8 7.59 6.49 <5 6.45 <5 5.59 <5 <5<5 483 8.82 8.74 8.88 8.32 7.69 6.41 <5 6.82 <5 5.68 <5 <5 <5 485 8.258.16 7.97 7.3 7.75 7.33 <5 7.39 <5 5.91 <5 5.13 <5 486 8.57 8.45 8.387.7 7.01 6.34 <5 6.71 <5 5.17 <5 <5 <5 487 8.35 8.36 8.29 7.62 7.48 6.35<5 6.4 ~5.25 ~5.56 <5 ~5.14 ~5 488 7.99 8.12 8.02 7.26 6.73 6.11 <5 6.5<5 5.32 <5 <5 <5 7.92 7.88 8.01 7.41 6.65 5.7 <5 6.58 <5 5.13 <5 <5 <5489 8.9 8.55 8.79 8.11 7.54 7.42 <5 7.9 <5 6.34 <5 ~5.1 <5 490 8.62 8.658.5 7.88 6.9 7.02 <5 7.26 <5 5.78 <5 <5 <5 493 8.67 8.53 8.57 7.95 6.997.27 <5 7.35 <5 5.79 <5 5.25 <5 494 9.21 8.64 8.99 8.26 7.69 7.11 <57.22 <5 6 <5 ~5.11 <5 495 8.17 8.35 8.24 7.58 6.93 6.7 <5 6.9 <5 5.47 <5<5 <5 137 8.79 8.47 8.37 8.12 6.98 7.57 <5 7.74 <5 5.88 <5 <5 <5 119 7.87.89 7.64 6.92 6.13 5.71 <5 5.94 <5 <5 <5 <5 <5 498 8.33 8.3 8.42 6.857.05 6.73 <5 7.06 <5 5.65 <5 5.01 <5 99 9.07 8.72 9.09 8.95 7.02 7.54 <58.12 <5 5.63 <5 <5 <5 8.99 8.79 9.19 8.79 7.29 7.73 <5 8.11 <5 5.59 <5<5 <5 138 8.5 8.32 8.56 7.06 7.34 6.92 <5 6.98 <5 6.16 <5 5.39 <5 8.348.3 8.52 7.07 7.16 6.64 <5 7.11 <5 5.81 <5 5.11 <5 8.53 8.5 8.6 7.137.49 6.95 ~5.18 6.83 5.25 6.21 5.29 5.61 5.17 499 8.74 8.4 8.56 8.13 7.57.39 <5 7.7 <5 6.09 <5 ~5.16 <5 500 8.73 8.55 8.58 7.36 7.66 7.06 <57.24 <5 6.29 <5 <5 <5 8.71 8.15 8.62 7.53 7.71 501 8.7 8.75 8.56 7.957.12 7.19 <5 7.08 <5 5.88 <5 <5 <5 502 8.76 8.75 8.62 8.06 7.2 7.44 <57.49 <5 5.96 <5 <5 <5 503 8.91 8.74 8.96 8.65 7.83 7.83 <5 7.9 <5 6.32<5 <5 <5 139 8.18 8.28 8.39 7.87 6.86 7.02 <5 6.97 <5 5.29 <5 <5 <5 5049.06 8.9 8.93 8.27 7.39 7.01 <5 6.62 <5 5.15 <5 <5 <5 8.99 8.82 8.83 8.17.39 6.95 <5 6.71 <5 5.16 <5 <5 <5 140 8.22 8.33 8.5 8.07 7.12 6.42 <57.04 <5 5.5 <5 <5 <5 8.59 8.68 8.71 8.16 7.48 6.82 <5 7.16 <5 5.53 <5 <5<5 506 7.55 7.91 7.87 6.92 6.7 6.13 <5 6.27 <5 5.37 <5 <5 <5 507 8.18.22 8.22 7.32 6.66 6.51 <5 6.41 <5 5.22 <5 <5 <5 508 7.56 7.89 7.966.97 7.07 6.44 <5 6.19 <5 5.31 <5 <5 <5 509 8.57 8.43 >8 <5 7.05 <5 5.31<5 510 8.25 8.34 8.1 7.34 6.89 6.95 <5 6.76 <5 5.53 <5 <5 <5 141 9.018.82 9.22 8.42 7.63 7.49 <5 7.58 <5 6.16 <5 <5 <5 8.9 8.45 8.92 8.377.49 6.86 <5 6.99 <5 5.68 <5 <5 <5 511 8.08 8.13 8 7.55 7.46 7.71 <5 8.1<5 6.94 <5 5.68 <5 512 8.6 8.62 8.52 7.88 7.13 7.72 <5 7.75 <5 5.73 <5<5 <5 513 8.86 8.7 9.08 8.17 7.27 7.12 <5 7.15 <5 5.68 <5 <5 <5 514 8.318.56 8.45 7.81 7.51 6.91 <5 7 <5 5.94 <5 <5 <5 515 7.77 7.94 7.47 6.736.63 6.13 ~5.24 6.34 5.29 ~5.45 5.19 ~5.33 ~5.09 35 7.3 7.45 7.32 6.396.21 5.72 <5 5.64 <5 5.08 <5 5.41 <5 517 7.95 8.22 8.32 7.54 7.34 6.77<5 7.01 <5 5.89 <5 <5 <5 518 8.37 8.55 8.2 7.43 7.2 7.02 <5 7.58 5.26.08 <5 5.25 <5 519 8.74 8.62 8.62 8.1 7.07 7.5 <5 7.3 <5 5.74 <5 <5 <5102 8.53 8.47 8.52 7.78 7.24 7.07 <5 7.37 <5 5.93 <5 <5 <5 521 8.76 8.778.56 8.42 7.74 8.17 <5 8.19 <5 6.3 <5 5.01 <5 522 8.71 8.51 8.51 7.936.98 7.52 <5 7.58 <5 ~6.02 <5 <5 <5 523 8.14 8.42 8.44 8.08 6.68 6.6 <56.84 <5 5.22 <5 <5 <5 142 8.36 8.39 8.53 7.97 6.75 6.7 <5 6.94 <5 5.48<5 <5 <5 524 8.75 8.55 8.71 8.11 7.61 6.85 <5 7.2 <5 5.75 <5 <5 <5 5258.03 8.43 8.49 7.72 6.64 6.73 <5 7.05 <5 5.54 <5 <5 <5 526 8.29 8.478.32 7.76 7.07 7.42 <5 7.48 <5 5.86 <5 <5 <5 527 8.18 8.26 8.42 7.777.69 6.32 <5 6.67 ~5.01 5.94 ~5.02 5.11 <5 143 8.01 8.21 7.95 7.3 7.036.66 <5 7.02 <5 5.75 <5 <5 <5 528 8.44 8.58 8.24 7.54 7.44 6.89 <5 7.18<5 6.19 <5 <5 <5 529 8.64 8.52 8.47 8.06 7.35 7.27 <5 7.51 5.13 6.07 ~55.12 <5 530 8.44 8.59 8.43 7.62 7.46 6.92 <5 7.34 5.21 6.34 <5 5.1 <5 108.21 8.12 8.21 7.96 6.43 6.97 <5 7.13 <5 <5 <5 <5 <5 531 8.57 8.67 8.657.97 7.34 7.36 <5 7.68 <5 6.24 <5 <5 <5 36 7.97 8.29 8.66 7.6 6.84 6.35<5 6.59 <5 5.52 <5 5.13 <5 532 7.28 7.36 7.22 6.47 6.24 5.82 <5 6.09 <5<5 <5 <5 <5 533 8.76 8.65 8.49 8.01 7.34 7.37 <5 7.63 <5 6.31 <5 <5 <5534 8.63 8.66 8.46 7.92 7.1 7.41 <5 7.74 <5 6.16 <5 <5 <5 535 8.81 8.78.4 8.18 7.43 7.48 <5 7.99 5.15 6.35 <5 <5 <5 536 7.03 7.33 7.7 6.76 <65.66 <5 5.85 <5 <5 <5 <5 <5 537 8.16 8.14 7.93 7.23 6.95 6.2 <5 6.18 <55.33 <5 5.12 <5 538 7.25 7.52 7.8 6.99 6.38 5.39 <5 5.44 <5 5.18 <5 <5<5 7.25 7.52 7.8 6.99 6.38 5.39 <5 5.44 <5 5.18 <5 <5 <5 144 7.92 8.318.41 7.52 7 6.45 <5 6.58 <5 5.34 <5 <5 <5 539 7.76 8.1 7.79 7.15 6.356.5 <5 6.65 <5 5.35 <5 <5 <5 603 8.53 8.56 8.22 7.6 7.14 7.52 <5 7.51 <55.74 <5 <5 <5 540 8.32 8.28 8.35 7.57 6.68 7.24 <5 7.37 <5 5.5 <5 <5 <5541 8.62 8.81 8.66 8.13 7.56 7.67 <5 7.83 <5 6.38 <5 <5 <5 542 8.52 8.58.59 8.24 7.14 6.67 <5 6.77 <5 5.11 <5 <5 <5 543 8.7 8.54 8.39 7.73 7.187.52 <5 7.62 <5 5.68 <5 <5 <5 544 8.14 8.11 7.71 7.08 6.71 6.66 <5 6.79<5 5.37 <5 <5 <5 41 8.73 8.78 8.83 8.3 7.57 7.35 <5 7.36 <5 5.93 <5 <5<5 33 8.73 8.75 8.51 8.17 7.47 7.88 <5 7.87 <5 6.02 <5 5.07 <5 43 8.558.62 8.24 7.6 7.16 6.94 ~5.26 7.04 ~5.34 5.65 ~5.3 ~5.42 ~5.27 546 8.698.6 8.45 8.15 6.9 8.31 <5 8.09 <5 5.56 <5 <5 <5 547 7.48 7.62 7.86 6.896.58 6.13 <5 6.3 <5 <5 <5 <5 <5 548 8.53 8.71 8.39 8.13 7.18 7.86 <57.96 ~5.14 5.89 ~5.02 5.14 <5 551 8.33 8.51 8.6 7.72 7.63 6.88 <5 7.1 <55.95 <5 <5 <5 552 8.14 8.4 8.01 7.11 7.43 7.35 <5 7.07 <5 6.08 <5 5.09<5 553 8.31 8.36 8.27 7.85 7.17 7.26 <5 7.2 <5 5.88 <5 <5 <5 554 8.148.32 8.22 7.89 7.2 7.14 <5 7.07 <5 6 ~5.04 5.15 <5 556 7.88 8.15 8.017.38 6.93 6.23 <5 6.21 <5 5.16 <5 <5 <5 557 7.82 8.12 8.01 6.97 6.616.09 <5 6.22 <5 <5 <5 <5 <5 558 8.39 8.56 8.32 7.66 6.78 7.01 <5 6.99~5.17 5.55 5.09 5.44 <5 103 8.7 8.73 8.75 8.06 7.47 7.37 <5 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7.03 6.52 5.28 <5 5.27 <5 <5 <5 <5 <5 604 9.12 8.47 8.51 8.347.65 ~7.59 <5 ~7.54 <5 6.06 <5 5.07 <5 608 8.33 8.12 8 7.35 6.99 6.7 <56.88 <5 5.07 <5 <5 <5 609 8.42 8.13 8.09 7.42 6.91 6.63 <5 6.6 <5 5.22<5 5.06 5 610 8.68 8.21 8.29 7.68 7.25 6.92 <5 ~7.13 <5 5.14 <5 <5 <5611 8.47 8.12 8.29 7.83 6.57 6.63 <5 6.93 <5 <5 <5 <5 <5 697 8.66 8.378.4 7.89 7.26 7.26 <5 6.7 <5 5.82 <5 <5 <5 698 8.85 8.31 8.28 7.94 7.17.3 <5 ~8.18 <5 5.95 <5 <5 <5 699 8.82 8.36 8.42 7.78 7.19 ~7.43 <5~7.54 <5 5.57 <5 ~5 <5 700 9.01 8.47 8.52 8.15 ~6 7.98 5.26 8.27 <5 <5<5 5.25 <5 8.57 8.09 8.32 7.99 6.5 7.79 5.25 ~8.49 <5 <5 <5 5.4 <5 6138.39 7.91 8.42 7.5 7.08 6.35 <5 ~6.61 <5 5.13 <5 <5 <5 701 8.26 8 7.846.94 ~6.23 6.81 <5 6.89 <5 <5 <5 <5 <5 702 8.1 7.94 8.28 7.49 6.96 6.01<5 6.57 <5 <5 <5 <5 <5 703 8.32 8.03 8.61 8.25 7.07 6.98 <5 7.22 <5 5.12<5 <5 <5 645 8.6 8.28 8.66 7.66 7.41 7.27 <5 ~6.95 <5 5.83 <5 5.85 <5704 8.38 8.07 8.59 7.88 7.24 6.26 <5 6.94 <5 5.28 <5 5.07 <5 15 8.157.92 8.28 7.41 6.87 6.36 <5 6.53 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8.758.47 8.15 7.69 <6 7.16 5.17 6.99 ~5.08 5.75 ~5 5.19 5.02 765 7.98 8.018.19 7.54 7.41 7.18 <5 7.63 <5 5.08 <5 5.12 <5 766 6.87 6.64 6.71 6.27<6 <5 <5 <5 <5 <5 <5 <5 <5 767 8.19 7.79 7.89 7.45 6.7 7.07 5.69 7.28~5.56 <5 5.6 5.67 5.53 768 8.6 8.16 8 7.16 <6 6.46 <5 6.38 <5 5.31 <5 <5<5 770 8.74 8.48 7.98 7.69 7.78 7.5 <5 ~7.62 <5 5.65 ~5 <5 <5 644 8.818.29 8.62 7.69 <6 7.22 <5 7.1 <5 5.62 <5 <5 <5 656 8.59 8.46 8.96 8.146.81 7.16 <5 ~7.63 <5 5.49 <5 5.11 <5 8.73 8.5 9.29 8.38 7.28 7.21 <57.46 <5 5.64 <5 5.21 <5 657 8.32 8.27 8.6 7.61 <6 7 <5 7.14 <5 5.56 <5<5 <5 8.58 8.38 8.87 7.87 7.32 7.15 <5 7.28 <5 5.49 <5 <5 <5 658 8.418.23 7.95 7.48 6.85 7.33 <5 7.31 <5 5.56 <5 <5 <5 771 8.78 8.53 8.488.33 6.63 7.98 6.06 8.23 5.63 5.68 5.64 5.77 5.6 772 7.84 7.89 8.11 7.76<6 6.34 5.73 6.41 <5 5.88 5.36 6.07 5.74 7.91 7.99 8.33 7.58 6.99 6.326.09 6.36 <5 5.91 5.66 6.16 5.71 773 7.9 7.82 7.18 7.02 6.9 6.41 <5 6.51<5 5.11 <5 <5 <5 774 8 8.12 8.04 7.65 7.08 6.71 <5 6.75 <5 5.37 <5 5.02<5 627 8.4 8.43 8.21 7.65 6.86 6.75 <5 6.53 <5 5.17 <5 <5 <5 775 8.48.47 8.69 7.9 7.44 7.17 <5 7.21 <5 5.74 <5 5.16 <5 777 7.28 7.36 7.556.85 ~6.54 6.98 <5 7.51 <5 <5 <5 <5 <5 778 7.52 7.44 7.26 6.5 6.17 7.58<5 7.73 <5 5.25 <5 <5 <5 779 7.41 7.23 7.02 6.32 ~6 6.6 <5 6.74 <5 <5 <5<5 <5 628 7.43 7.32 7.46 6.75 6.69 6.57 <5 6.69 <5 5.16 <5 <5 <5 6297.59 7.59 7.66 6.7 6.64 6.83 <5 7.04 <5 5.08 <5 <5 <5 780 8.66 8.23 8.468.32 7.05 7.7 <5 ~7.96 <5 5.37 <5 <5 <5 781 8.23 8.11 8.34 7.78 6.867.08 <5 7.15 <5 5.14 <5 <5 <5 782 8.66 8.38 8.13 7.78 7.74 7.59 <5 7.44<5 5.86 <5 <5 <5 634 8.05 7.82 7.75 7.56 <6 7.96 5.23 8.03 <5 <5 <5 5.05<5 783 7.69 7.67 7.81 6.73 6.7 6.3 <5 6.24 <5 5.31 <5 <5 <5 784 7.087.15 7.21 6.82 6.42 5.4 <5 5.88 <5 <5 <5 <5 <5 785 8.18 7.91 7.84 7.457.11 8.58 <5 8.23 <5 5.06 <5 <5 <5 786 7.9 7.79 7.89 7.46 6.32 7.72 5.167.97 <5 5.07 5.05 5.13 5.02 787 7.56 7.36 7.48 7.17 6.26 7.31 5.13 7.72<5 5.11 5.07 5.12 ~5 788 8.62 8.34 8.28 7.83 6.27 8.35 5.11 8.47 <5 5.05<5 5.13 <5 789 8.75 8.23 8.33 8.01 6.1 8.55 <5 8.61 <5 <5 <5 <5 <5 7906.56 6.59 6.53 <6 <6 5.21 <5 5.23 <5 <5 <5 <5 <5 791 7.9 7.77 7.68 7.836.86 8.11 5.17 8.38 <5 5.66 5.04 5.2 <5 792 7.81 7.69 7.73 7.4 6.45 7.335.43 7.75 <5 5.51 ~5 5.34 5.12 793 7.15 7.05 6.92 6.64 <6 6.94 5.72 7.325.38 5.41 5.38 5.5 5.4 631 8.15 8.24 7.53 6.89 6.47 6.51 5.2 6.49 ~5.145.33 ~5.1 5.29 ~5.09 794 7.78 7.85 7.48 6.84 6.06 6.16 <5 6.11 <5 <5 <5<5 <5 795 8.5 8.15 8.18 8.3 5.71 8.32 5.36 8.63 ~5.18 5.3 5.27 5.43~5.25 796 7.21 7.05 7.12 6.76 6.1 6.83 <5 7.23 <5 <5 <5 <5 <5 798 7.537.66 7.72 7.06 6.02 6.08 <5 6.33 <5 <5 <5 <5 <5 659 8.26 8.11 8.59 7.566.75 6.69 <5 7.12 <5 5.15 <5 5.01 <5 662 7.55 7.69 7.63 7.26 7.11 6 <56.21 <5 5.27 <5 <5 <5 799 7.42 7.6 7.57 7.13 6.95 6.76 <5 6.87 <5 5.52<5 <5 <5 661 8.71 8.53 8.63 7.72 7.05 6.72 <5 6.66 <5 <5 <5 <5 <5 6608.98 8.6 8.9 8.09 7.23 7.16 <5 7.14 <5 5.18 <5 <5 <5 633 8.29 8.37 8.537.81 6.81 6.76 <5 6.85 <5 5.38 <5 <5 <5 800 7.9 7.8 7.74 7.28 6.44 6.665.47 6.85 ~5.33 5.48 5.5 5.42 5.41 801 7.58 7.55 7.65 7.19 6.49 5.74 <55.77 <5 <5 <5 <5 <5 802 8.68 8.44 8.85 7.77 7.25 6.71 <5 6.99 <5 5.17 <5<5 <5 803 8.4 8.14 8.42 7.16 7.02 6.59 <5 6.67 <5 5.16 <5 <5 <5 636 7.357.4 7.12 6.5 6.01 5.66 <5 5.95 <5 5.11 <5 <5 <5 637 7.11 7.33 6.94 6.68<6 5.65 <5 6.05 <5 <5 <5 <5 <5 804 8.16 8.02 7.72 7.5 <6 8.44 5.12 8.61<5 5.15 5.09 5.1 5.06 805 7.71 7.63 7.59 7.33 <6 7.13 <5 7.63 <5 <5 <5<5 <5 806 7.04 6.75 6.75 <6 <6 5.14 <5 5.06 <5 <5 <5 <5 <5 807 7.05 6.867 6.71 <6 5.58 <5 5.79 <5 <5 <5 <5 <5 808 7.32 7.03 7.14 6.6 6.19 5.96<5 6 <5 5.22 <5 5.04 <5 809 7.89 7.49 7.73 7.32 6.02 7.47 5.23 ~7.53 <55.09 5.11 5.13 5.01 810 7.73 7.67 7.88 7.2 6.91 6.26 5.59 6.24 <5 5.71<5 5.28 <5 635 8.05 7.97 7.94 7.48 6.75 6.59 <5 ~6.53 <5 5.25 <5 <5 <5811 7.58 7.47 7.6 7.09 6.78 6.14 <5 ~6.03 <5 5.15 <5 <5 <5 812 8.25 8.098.03 7.19 6.72 7.07 <5 6.8 <5 5.21 <5 <5 <5 813 8.86 8.59 8.8 8.67 7.938.63 <5 8.27 <5 6.87 <5 5.5 <5 814 7.35 7.47 7.56 7.18 <6 7.03 5.1 7.14<5 5.03 <5 <5 <5 815 7.48 7.62 7.82 7.03 6.37 6.42 <5 6.3 <5 <5 <5 <5 <5816 6.96 7.09 7.29 6.63 ~6.03 6.81 <5 6.93 <5 <5 <5 <5 <5 817 7.65 7.597.77 7.27 6.25 7.35 5.12 ~7.49 <5 <5 <5 <5 <5 640 7.25 7.64 7.72 7.416.61 5.82 <5 5.62 <5 <5 <5 <5 <5 819 7.74 7.78 7.93 6.95 7.12 6.28 <56.17 <5 5.47 <5 <5 <5 687 8.75 8.45 8.31 7.95 7.76 >8 5.22 >8 <5 7.61 <55.85 <5 820 6.79 7.08 7.04 6.27 <6 5.74 <5 5.81 <5 <5 <5 <5 <5 632 8.818.63 8.92 7.86 6.98 7.23 5.16 7.03 <5 5.69 <5 5.1 <5 821 8.86 8.53 8.688.56 7.85 >8 <5 >8 <5 6.61 <5 4.99 <5 822 9.03 8.79 9.1 8.45 7.65 7.82<5 7.66 <5 6.2 <5 5.19 <5 823 7.13 6.92 7.08 6.31 <6 5.71 <5 5.7 <5 <5<5 <5 <5 824 7.36 7.49 7.57 7.12 <6 6.04 <5 6.1 <5 <5 <5 <5 <5 825 8.088.24 8.47 7.86 7.04 6.64 <5 6.81 <5 5.3 <5 <5 <5 826 8.76 8.51 8.62 8.367.64 9.22 5.14 9.41 <5 5.97 5.09 5.32 <5 827 8.73 8.47 8.64 8.5 7.58 9.25.33 9.42 5.01 6.33 5.3 5.48 5.15 828 8.28 8.28 8.8 7.69 7.07 7.12 <57.22 <5 5.62 <5 <5 <5 829 7.82 7.52 7.54 7 <6 8.22 5.34 8.43 <5 5.11 ~55.07 <5 830 7.54 7.6 7.62 6.87 6.15 663 8.81 8.71 ~8.95 8.32 7.39 7.55<5 ~7.61 <5 6.66 <5 <5 <5 664 7.79 ~7.69 7.98 7 ~6.61 5.64 <5 5.34 5.03<5 <5 <5 <5 831 7.69 ~8 7.75 7.21 6.42 6.13 5.38 6.76 5.44 5.19 5.23 5.55.3 832 6.45 6.61 6.43 <6 <6 5.02 <5 <5 <5 <5 <5 <5 <5 833 7.29 7.43 7.4~6.5 6.98 5.54 <5 5.78 <5 5.11 <5 <5 <5 834 7.98 8.25 8.48 7.79 6.717.07 <5 7.25 <5 5.11 <5 <5 <5 837 8.73 ~8.85 8.6 7.88 7.68 641 9 ~9.058.92 8.25 7.43 7.5 <5 6.22 <5 <5 <5 642 8.86 8.98 8.77 8.42 7.74 >8 <56.42 <5 <5 <5 838 8.6 7.85 7.05 <5 5.98 <5 <5 <5 839 <6 <6 <5 <5 <5 <5<5 <5 840 8.51 8.13 >8 <5 6.57 <5 5.16 <5 881 5.1 5.2 <5 <5 5.8 <5 <5 <5<5 <5 <5 <5 <5 882 5.3 5.4 5.4 5.1 5.3 <5 <5 <5 <5 <5 <5 <5 <5 883 5.75.8 5.7 <5 6.2 <5 <5 <5 <5 <5 <5 <5 <5 884 6.0 6.3 6.1 5.5 6.2 <5 <5 <5<5 <5 <5 <5 <5 885 7.17 6.92 7.33 6.5 <6 5.33 <5 <5 <5 <5 <5 886 7.447.67 7.76 7.06 6.31 ~5.49 <5 5.91 <5 <5 <5 <5 <5 887 7.41 7.6 7.75 6.916.29 5.51 <5 5.71 <5 <5 <5 <5 <5 888 6.8 7.07 6.74 <6 <6 5.4 <5 ~5.14 <5<5 <5 <5 <5 889 8.38 8.38 8.39 7.14 7.26 5.27 <5 5.71 <5 <5 <5 <5 <5 8906.46 6.62 6.42 <6 6.21 <5 <5 <5 <5 <5 <5 <5 <5 891 7.44 7.43 7.36 6.87<6 5.96 <5 6.15 <5 <5 <5 5.02 <5 892 6.69 6.89 6.65 <6 <6 <5 <5 <5 <5 <5<5 <5 <5 893 6.36 6.38 6.34 <6 6.09 5.04 <5 5.01 <5 <5 <5 5.07 <5 8946.98 6.73 6.55 <6 <6 895 7.26 7.16 7.49 6.64 <6 5.44 <5 5.55 <5 <5 <5 <5<5 896 8.47 7.96 7.98 7.4 6.7 6.87 <5 6.87 <5 5.46 <5 <5 <5 897 8.87 88.34 7.9 6.83 7.14 <5 7.23 <5 5.59 <5 <5 <5 898 6.77 6.63 6.45 <6 6.165.15 <5 ~5.12 <5 <5 <5 <5 <5 899 7.09 6.78 6.76 6.42 <6 5.39 <5 5.22 <5<5 <5 <5 <5 900 7.62 7.53 7.54 6.66 <6 5.32 <5 5.33 <5 <5 <5 <5 <5 9017.78 7.7 8.27 7.32 <6 6.37 <5 6.56 <5 <5 <5 <5 <5 902 8.48 8.33 8.818.33 7.32 <5 <5 <5 <5 <5 <5 <5 <5 903 6.87 6.84 7.19 6.07 <6 <5 <5 <5 <5<5 <5 <5 <5 904 7.1 7.26 7.59 6.89 6.09 5.73 <5 6.01 <5 <5 <5 <5 <5 905<6 <6 <6 <6 6.14 <5 <5 <5 <5 <5 <5 5.26 5.05 906 7.7 7.21 7.35 6.63 6.255.21 <5 5.23 <5 <5 <5 <5 <5 907 6.92 6.35 6.91 6.35 <6 5.12 <5 ~5.09 <5<5 <5 <5 <5 908 7.21 6.55 6.83 6.49 <6 7.01 <5 5.41 <5 <5 <5 <5 <5 9096.83 6.83 6.84 6.52 <6 5.2 <5 ~5.03 <5 <5 <5 <5 <5 910 6.66 6.18 6.336.04 <6 5.12 <5 <5 <5 <5 <5 <5 <5 911 6.76 6.57 6.56 6.47 <6 5.04 <55.06 <5 <5 <5 <5 <5 912 7.19 7.11 7.29 6.64 6.26 5.59 <5 5.65 <5 <5 <5<5 <5 913 <6 ~6 <6 <6 <6 5.1 <5 5.05 <5 <5 <5 <5 <5 914 6.8 6.72 6.21 <6<6 5.08 <5 5.09 <5 <5 <5 <5 <5 915 <6 <6 <6 <6 <6 <5 <5 <5 <5 <5 <5 <5<5 916 8 7.69 7.86 7.23 6.63 6.91 <5 6.81 <5 5.26 <5 <5 <5 917 <6 <6 <6<6 <6 <6 <5 6.09 <5 <5 <5 <5 <5 918 7.04 6.99 7.21 6.42 6.08 5.7 <5~5.63 <5 <5 <5 <5 <5 919 6.59 6.53 6.91 <6 <6 <5 <5 ~5.05 <5 <5 <5 <5 <5920 7.39 7.15 6.87 ~6.31 5.6 <5 <5 <5 <5 <5 921 ~6.63 6.47 <5 <5 <5 <5<5 <5 922 6.92 7.21 6.75 <5 <5 <5 <5 <5 923 7.44 7.67 7.76 7.06 6.31~5.49 <5 5.91 <5 <5 <5 <5 <5 924 7.44 7.43 7.36 6.87 <6 5.96 <5 6.15 <5<5 <5 5.02 <5 926 6.69 6.89 6.65 <6 <6 <5 <5 <5 <5 <5 <5 <5 <5 925 6.986.73 6.55 <6 <6

Biological Assays B FGFR3, VEGFR2 and PDGFR In Vitro Kinase InhibitoryActivity Assays

Enzymes (from Upstate), prepared at 2× final concentration, wereincubated with test compounds, biotinylated Flt3 substrate(biotin-VASSDNEYFYVDF) (Cell Signalling Technology Inc.) and ATP in theappropriate assay buffer (Table 1). The reaction was allowed to proceedfor 3 hours (FGFR3), 1 hour (VEGFR2, PDGFR-beta) at room temperature ona plate shaker at 700 rpm before being stopped with 35 mM EDTA, pH 8(FGFR3, VEGFR2) or 55 mM EDTA, pH 8 (PDGFR-beta). 5× detection mix (50mM HEPES pH 7.5, 0.1% BSA, 11.34 nM Eu-anti-pY (PY20) (PerkinElmer) 74nM SA-XL665 (Cisbio) for FGFR3, 50 mM HEPES, pH 7.5, 0.1% BSA, 11.34 nMEu-anti-pY (PY20), 187.5 nM SA-XL665 for VEGFR2 and 50 mM HEPES, pH 7.5,0.1% BSA, 11.34 nM Eu-anti-pY (PT66) (PerkinElmer), 375 nM SA-XL665(Cisbio) for PDGFR-beta) was then added to each well and the platesealed and incubated at room temperature for one hour on a plate shakerat 700 rpm. The plate was then read on a Packard Fusion plate reader ora BMG Pherastar both in TRF mode.

TABLE 1 Final assay conditions for FGFR3, VEGFR2 and PDGFR-beta assaysFlt3 substrate ATP Enzyme 1 × Assay Buffer concentration concentrationFGFR3 A 0.125 μM 8 μM VEGFR2 B 0.5 μM 0.5 μM PDGFR-beta C 1 μM 70 μMKinase Assay buffers were:

A: 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.01% TritonX-100

B: 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.01% TritonX-100, 0.1 mMSodium orthovanadateC: 20 mM HEPES pH 7.5, 10 mM MnCl₂, 0.01% Triton X-100, 1 mM DTT, 0.1 mMSodium orthovanadate

FGFR3 and VEGFR2Data for the compounds of the invention in the aboveassays are provided in Table A3.

Ba/F3-TEL-FGFR3 & Ba/F3 (WT) Cell Proliferation Assays

Stably transfected Ba/F3-TEL-FGFR3 cells were plated out into black96-well tissue culture plates with clear bottoms in RPMI mediumcontaining 10% FBS and 0.25 mg/ml G418 at a density of 5×10³ cells/well(200 μl per well). The parental wild-type Ba/F3 cells (DSMZ no.: ACC300) were plated out into black 96-well tissue culture plates with clearbottoms in RPMI medium containing 10% FBS and 2 ng/ml mouse IL-3 (R&DSysems) at a density of 2.5×10³ cells/well (200 μl per well). Plateswere placed in an incubator overnight before adding the compounds thefollowing day. Dilutions of compounds were made in DMSO starting at 10mM and were diluted into the wells to give a final DMSO concentration of0.1% in assay. Compounds were left on the cells for 72 hours before theplates were removed from the incubator and 20 μl of Alamar Blue™(Biosource) was added to each well. Plates were placed in the incubatorfor 4-6 hours before reading plates at 535 nm (excitation)/590 nm(emission) on a Fusion plate reader (Packard). Where inhibition is highan IC₅₀ can be determined.

Data for the compounds of the invention in the above assays are providedin Table A3.

TABLE A3 BAF3_TEL_ Compound FGFR3 VEGFR2 FGFR3 BAF3_WT number pIC₅₀ (μM)pIC₅₀ (μM) pIC₅₀ (μM) pIC₅₀ (μM) 201 8.96 7.31 7.89 5.55 12 8.09 6.667.27 5.44 13 7.77 5.96 6.85 215 6.21 222 7.89 5.85 6.74 5.24 228 7.225.96 19 8.30 6.72 6.74 5.77 24 6.77 7.43 247 6.77 7.43 70 & 70a 8.547.25 8.43 6.31 281 7.31 8.66 282 7.31 8.66 284 9.29 7.70 8.96 5.64 2859.29 7.70 8.96 5.64 88 & 291 9.19 8.05 9.24 5.72 305 8.72 6.30 7.58 618.29 6.80 6.46 5.72 306 7.51 5.82 6.89 307 5.72 6.46 308 8.82 7.57 8.57311 8.54 6.92 7.96 312 8.77 7.44 6.64 314 7.89 6.31 6.80 30 8.52 6.897.58 315 8.42 6.82 7.70 48 7.92 8.92 316 7.80 9.05 328 8.85 7.80 8.065.96 329 8.85 7.80 8.06 5.96 331 8.74 7.48 8.60 5.13 332 8.74 7.48 8.605.13 371 8.87 7.44 8.20 6.21 372 8.87 7.44 8.20 6.21 374 8.62 6.68 8.21377 8.49 6.92 8.38 380 9.09 7.64 8.77 5.04 381 8.82 7.17 8.42 108 9.217.52 383 9.21 7.52 384 8.80 7.23 9.05 5.28 39 8.58 6.82 7.96 40 8.216.37 7.66 386 7.57 6.17 6.92 6.08 389 9.15 6.72 8.43 390 7.57 9.23 3918.15 7 7.31 392 8.44 7.04 7.92 5.72 393 8.44 7.04 7.92 5.72 404 7 5.82405 7 5.82 409 9.05 6.70 8.89 5.60 410 9.05 6.70 8.89 5.60 423 7.68 9.175.72 424 7.68 9.17 5.72 426 6.82 5.77 427 6.82 5.77 463 7.47 9.34 6.35466 7.47 9.41 5.46 467 7.47 9.41 5.46 470 & 471 8.74 7.09 8.96 5.80 4729 7.60 9.04 473 9 7.60 9.04 484 8.70 9.10 6.23 509 8.28 516 5.72 5.21516 7 6.70

1. A method for treating a subject suffering from, or being at risk ofsuffering from a disease state or condition mediated by a FGFR kinase,said method comprising administering to the subject a compound selectedfrom the group consisting of a compound of formula (I)

a tautomeric form, stereochemically isomeric form and isotopic formthereof, wherein n is an integer equal to 0, 1, 2, 3 or 4; R¹ ishydrogen, C₁₋₆alkyl, C₂₋₄alkenyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl is optionally substituted with one or two hydroxyl groups,C₁₋₆alkyl substituted with —NR⁴R⁵, C₁₋₆alkyl substituted with—C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkylsubstituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶,C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkyl substituted with—P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; eachR^(1a) is independently selected from hydrogen, C₁₋₄alkyl,hydroxyC₁₋₄alkyl, C₁₋₄alkyl substituted with amino or mono- ordi(C₁₋₄alkyl)amino or —NH(C₃₋₈cycloalkyl), cyanoC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more fluoroatoms; each R² is independently selected from hydroxyl, halogen, cyano,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, hydroxyhaloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, haloC₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl is optionally substitutedwith one or two hydroxyl groups, hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl, R¹³,C₁₋₄alkyl substituted with R¹³, C₁₋₄alkyl substituted with —C(═O)—R¹³,C₁₋₄alkoxy substituted with R¹³, C₁₋₄alkoxy substituted with —C(═O)—R¹³,—C(═O)—R¹³, C₁₋₄alkyl substituted with —NR⁷R⁸, C₁₋₄alkyl substitutedwith —C(═O)—NR⁷R⁸, C₁₋₄alkoxy substituted with —NR⁷R⁸, C₁₋₄alkoxysubstituted with —C(═O)—NR⁷R⁸, —NR⁷R⁸ and —C(═O)—NR⁷R⁸; or when two R²groups are attached to adjacent carbon atoms they are optionally takentogether to form a radical of formula: —O—(C(R¹⁷)₂)_(p)—O—; —X—CH═CH—;or —X—CH═N—; wherein R¹⁷ is hydrogen or fluorine, p is 1 or 2 and X is Oor S; R³ is hydroxyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxysubstituted with —NR¹⁰R¹¹, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,haloC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl, hydroxyhaloC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with carboxyl, C₁₋₆alkylsubstituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl isoptionally substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynylsubstituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted withhydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogensand —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; R⁴ and R⁵ are eachindependently hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl isoptionally substituted with one or two hydroxyl groups,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵, R¹³ or C₁₋₆alkyl substituted with R¹³; R⁶ isC₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to 7-membered monocyclicheterocyclyl containing at least one heteroatom selected from N, O andS; said C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to 7-memberedmonocyclic heterocyclyl, each optionally and each independentlysubstituted by 1, 2, 3, 4 or 5 substituents, each substituentindependently selected from cyano, C₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyl,carboxyl, hydroxyC₁₋₆alkyl, halogen, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl,C₁₋₆alkyl-O—C(═O)—, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —C(═O)—NR¹⁴R¹⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl and C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵; R⁷ and R⁸ are each independently hydrogen,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl orC₁₋₆alkoxyC₁₋₆alkyl; R⁹ is C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl,naphthyl, or 3 to 12 membered monocyclic or bicyclic heterocyclylcontaining at least one heteroatom selected from N, O and S, saidC₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, naphthyl, or 3 to 12 memberedmonocyclic or bicyclic heterocyclyl each optionally and eachindependently substituted with 1, 2, 3, 4 or 5 substituents, eachsubstituent independently selected from ═O, C₁₋₄alkyl, hydroxyl,carboxyl, hydroxyC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, C₁₋₄alkyl-O—C(═O)—,C₁₋₄alkyl substituted with C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkyl-C(═O)—,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl is optionally substitutedwith one or two hydroxyl groups, halogen, haloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkyl, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, —C₁₋₄alkyl substitutedwith —NR¹⁴R¹⁵, C₁₋₄alkyl substituted with —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkoxy,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂-haloC₁₋₄alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkylsubstituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with—NH—S(═O)₂—C₁₋₄alkyl, C₁₋₄alkyl substituted with—NH—S(═O)₂-haloC₁₋₄alkyl, C₁₋₄alkyl substituted with —NH—S(═O)₂—NR¹⁴R¹⁵,R¹³, —C(═O)—R¹³, C₁₋₄alkyl substituted with R¹³, phenyl optionallysubstituted with R¹⁶, phenylC₁₋₆alkyl wherein the phenyl is optionallysubstituted with R¹⁶, and a 5 or 6-membered aromatic monocyclicheterocyclyl containing at least one heteroatom selected from N, O and Swherein said heterocyclyl is optionally substituted with R¹⁶; or whentwo of the substituents of R⁹ are attached to the same atom, they areoptionally taken together to form a 4 to 7-membered saturated monocyclicheterocyclyl containing at least one heteroatom selected from N, O andS; R¹⁰ and R¹¹ are each independently hydrogen, carboxyl, C₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —C(═O)—NR¹⁴R¹⁵, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl is optionally substituted with one or two hydroxyl groups, R⁶,C₁₋₆alkyl substituted with R⁶, —C(═O)—R⁶, —C(═O)—C₁₋₆alkyl,—C(═O)-hydroxyC₁₋₆alkyl, —C(═O)-haloC₁₋₆alkyl,—C(═O)-hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with —Si(CH₃)₃,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵; R¹² is hydrogen or C₁₋₄alkyl optionally substitutedwith C₁₋₄alkoxy; R¹³ is C₃₋₈cycloalkyl or a saturated 4 to 6-memberedmonocyclic heterocyclyl containing at least one heteroatom selected fromN, O and S, wherein said C₃₋₈cycloalkyl or monocyclic heterocyclyl isoptionally substituted with 1, 2 or 3 substituents each independentlyselected from halogen, hydroxyl, C₁₋₆alkyl, —C(═O)—C₁₋₆alkyl,C₁₋₆alkoxy, and —NR¹⁴R¹⁵; R¹⁴ and R¹⁵ are each independently hydrogen,or haloC₁₋₄alkyl, or C₁₋₄alkyl optionally substituted with a substituentselected from hydroxyl, C₁₋₄alkoxy, amino and mono- ordi(C₁₋₄alkyl)amino; and R¹⁶ is hydroxyl, halogen, cyano, C₁₋₄alkyl,C₁₋₄alkoxy, —NR¹⁴R¹⁵ or —C(═O)NR¹⁴R¹⁵; or an N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof.
 2. Amethod according to claim 1, wherein the compound is selected from thegroup consisting of a compound of formula (I), a tautomeric form,stereochemically isomeric form and isotopic form thereof, wherein R¹ ishydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl is optionally substitutedwith one or two hydroxyl groups, C₁₋₆alkyl substituted with —NR⁴R⁵,C₁₋₆alkyl substituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —NH—S(═O)₂—C₁₋₆alkyl, R⁶, C₁₋₆alkyl substituted withR⁶, C₁₋₆alkyl substituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substitutedwith R⁶, or C₁₋₆alkyl substituted with —Si(CH₃)₃; each R^(1a) ishydrogen; R¹⁰ and R¹¹ are each independently hydrogen, C₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —C(═O)—NR¹⁴R¹⁵, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl is optionally substituted with one or two hydroxyl groups, R⁶,C₁₋₆alkyl substituted with R⁶, —C(═O)—R⁶, —C(═O)—C₁₋₆alkyl,—C(═O)-hydroxyC₁₋₆alkyl, —C(═O)-haloC₁₋₆alkyl,—C(═O)-hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with —Si(CH₃)₃,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵; or an N-oxide thereof, a pharmaceutically acceptablesalt thereof or a solvate thereof.
 3. A method according to claim 1,wherein the compound is selected from the group consisting of a compoundof formula (I), a tautomeric form, stereochemically isomeric form andisotopic form thereof, wherein each R^(1a) is hydrogen; or an N-oxidethereof, a pharmaceutically acceptable salt thereof or a solvatethereof.
 4. A method according to claim 1, wherein the compound isselected from the group consisting of a compound of formula (I), atautomeric form, stereochemically isomeric form and isotopic formthereof, wherein R¹ is C₁₋₆alkyl; or an N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof.
 5. Amethod according to claim 1, wherein the compound is selected from thegroup consisting of a compound of formula (I), a tautomeric form,stereochemically isomeric form and isotopic form thereof, wherein R¹ isCH₃— or CD₃-; or an N-oxide thereof, a pharmaceutically acceptable saltthereof or a solvate thereof.
 6. A method according to claim 1, whereinthe compound is selected from the group consisting of a compound offormula (I), a tautomeric form, stereochemically isomeric form andisotopic form thereof, wherein R² is independently selected fromhalogen, cyano, C₁₋₄alkyl, C₂₋₄alkenyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,hydroxyC₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, R¹³, C₁₋₄alkoxysubstituted with R¹³, —C(═O)—R¹³, C₁₋₄alkyl substituted with NR⁷R⁸,C₁₋₄alkoxy substituted with NR⁷R⁸, —NR⁷R⁸ and —C(═O)—NR⁷R⁸; or anN-oxide thereof, a pharmaceutically acceptable salt thereof or a solvatethereof.
 7. A method according to claim 6, wherein the compound isselected from the group consisting of a compound of formula (I), atautomeric form, stereochemically isomeric form and isotopic formthereof, wherein R² is C₁₋₄alkoxy; or an N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof.
 8. Amethod according to claim 6, wherein the compound is selected from thegroup consisting of a compound of formula (I), a tautomeric form,stereochemically isomeric form and isotopic form thereof, wherein R² isCH₃O— or CD30-; or an N-oxide thereof, a pharmaceutically acceptablesalt thereof or a solvate thereof.
 9. A method according to claim 1,wherein the compound is selected from the group consisting of a compoundof formula (I), a tautomeric form, stereochemically isomeric form andisotopic form thereof, wherein R³ is C₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl isoptionally substituted with one or two hydroxyl groups, C₁₋₆alkylsubstituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkylsubstituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with oneor two halogens and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,C₁₋₆alkyl substituted with carboxyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with hydroxyl and R⁹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹²,C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with—C(═O)—R⁹, C₂₋₆alkynyl substituted with R⁹, hydroxyC₁₋₆alkoxy,C₂₋₆alkenyl, C₂₋₆alkynyl or R¹³; or an N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof.
 10. Amethod according to claim 1, wherein the compound is selected from thegroup consisting of a compound of formula (I), a tautomeric form,stereochemically isomeric form and isotopic form thereof, wherein R¹ isC₁₋₆alkyl, each R^(1a) is hydrogen, n is an integer equal to 2, each R²is C₁₋₄alkoxy, and R³ is C₁₋₆alkyl substituted with —NR¹⁰R¹¹; or anN-oxide thereof, a pharmaceutically acceptable salt thereof or a solvatethereof.
 11. A method according to claim 10, wherein the compound isselected from the group consisting of a compound of formula (I), atautomeric form, stereochemically isomeric form and isotopic formthereof, wherein R¹⁰ is hydrogen, —CH₃, —CH₂CH₃ or —CH(CH₃)₂ and R¹¹ ishydrogen, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F,—C(═O)—CH₃, —S(═O)₂—CH₃, —S(═O)₂—CH₂CH₃, —S(═O)₂—CH(CH₃)₂,—S(═O)₂—N(CH₃)₂, —CH₂CH₂OH, —C(═O)—C(OH)(CH₃)CF₃, —C(═O)-cyclopropyl,—CH₂CH₂CN, cyclopropane, cyclopentane, 2,2,6,6-tetramethyl-piperidine,—CH₂C₃H₅, —CH₂— tetrahydrofuran, —C(═O)-(1-methyl-piperidin-3-yl),—C(═O)—CF₃, —CH₂Si(CH₃)₃, or —CH₂—C₆H₅; or an N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof.
 12. Amethod according to claim 10, wherein the compound is selected from thegroup consisting of a compound of formula (I), a tautomeric form,stereochemically isomeric form and isotopic form thereof, wherein R¹ is—CH₃, each R^(1a) is hydrogen, n is an integer equal to 2, each R² isCH₃O—, and R³ is —CH₂CH₂NHCH(CH₃)₂; or an N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof.
 13. Amethod according to claim 10, wherein the compound is selected from thegroup consisting of a compound of formula (I), a tautomeric form,stereochemically isomeric form and isotopic form thereof, wherein R¹ is—CH₃, each R^(1a) is hydrogen, n is an integer equal to 2, each R² isCH₃O—, and R³ is —CH₂CH₂—CH₂—NHCH₂CF₃ or —CH₂—CH₂NH₂; or an N-oxidethereof, a pharmaceutically acceptable salt thereof or a solvatethereof.
 14. A method according to claim 1, wherein the compound isN-(3,5-dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine;or an N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.
 15. A method according to claim 14, wherein thecompound isN-(3,5-dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine.16. A method according to claim 1, wherein the compound is selectedfrom:N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-N′-(2,2,2-trifluoroethyl)propane-1,3-diamine;andN-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine;or an N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.
 17. A method according to claim 16, wherein thecompound is selected from:N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-N′-(2,2,2-trifluoroethyl)propane-1,3-diamine;andN-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine.18. A method for treating a subject suffering from, or being at risk ofsuffering from cancer, said method comprising administering to thesubject a compound selected from the group consisting of a compound offormula (I)

a tautomeric form, stereochemically isomeric form and isotopic formthereof, wherein n is an integer equal to 0, 1, 2, 3 or 4; R¹ ishydrogen, C₁₋₆alkyl, C₂₋₄alkenyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl is optionally substituted with one or two hydroxyl groups,C₁₋₆alkyl substituted with —NR⁴R⁵, C₁₋₆alkyl substituted with—C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkylsubstituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶,C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkyl substituted with—P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; eachR^(1a) is independently selected from hydrogen, C₁₋₄alkyl,hydroxyC₁₋₄alkyl, C₁₋₄alkyl substituted with amino or mono- ordi(C₁₋₄alkyl)amino or —NH(C₃₋₈cycloalkyl), cyanoC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more fluoroatoms; each R² is independently selected from hydroxyl, halogen, cyano,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, hydroxyhaloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, haloC₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl is optionally substitutedwith one or two hydroxyl groups, hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl, R¹³,C₁₋₄alkyl substituted with R¹³, C₁₋₄alkyl substituted with —C(═O)—R¹³,C₁₋₄alkoxy substituted with R¹³, C₁₋₄alkoxy substituted with —C(═O)—R¹³,—C(═O)—R¹³, C₁₋₄alkyl substituted with —NR⁷R⁸, C₁₋₄alkyl substitutedwith —C(═O)—NR⁷R⁸, C₁₋₄alkoxy substituted with —NR⁷R⁸, C₁₋₄alkoxysubstituted with —C(═O)—NR⁷R⁸, —NR⁷R⁸ and —C(═O)—NR⁷R⁸; or when two R²groups are attached to adjacent carbon atoms they are optionally takentogether to form a radical of formula: —O—(C(R¹⁷)₂)_(p)—O—; —X—CH═CH—;or —X—CH═N—; wherein R¹⁷ is hydrogen or fluorine, p is 1 or 2 and X is Oor S; R³ is hydroxyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxysubstituted with —NR¹¹R¹¹, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,haloC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl, hydroxyhaloC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with carboxyl, C₁₋₆alkylsubstituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl isoptionally substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynylsubstituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted withhydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogensand —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; R⁴ and R⁵ are eachindependently hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl isoptionally substituted with one or two hydroxyl groups,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵, R¹³ or C₁₋₆alkyl substituted with R¹³; R⁶ isC₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to 7-membered monocyclicheterocyclyl containing at least one heteroatom selected from N, O andS; said C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to 7-memberedmonocyclic heterocyclyl, each optionally and each independentlysubstituted by 1, 2, 3, 4 or 5 substituents, each substituentindependently selected from cyano, C₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyl,carboxyl, hydroxyC₁₋₆alkyl, halogen, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl,C₁₋₆alkyl-O—C(═O)—, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —C(═O)—NR¹⁴R¹⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl and C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵; R⁷ and R⁸ are each independently hydrogen,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl orC₁₋₆alkoxyC₁₋₆alkyl; R⁹ is C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl,naphthyl, or 3 to 12 membered monocyclic or bicyclic heterocyclylcontaining at least one heteroatom selected from N, O and S, saidC₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, naphthyl, or 3 to 12 memberedmonocyclic or bicyclic heterocyclyl each optionally and eachindependently substituted with 1, 2, 3, 4 or 5 substituents, eachsubstituent independently selected from ═O, C₁₋₄alkyl, hydroxyl,carboxyl, hydroxyC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, C₁₋₄alkyl-O—C(═O)—,C₁₋₄alkyl substituted with C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkyl-C(═O)—,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl is optionally substitutedwith one or two hydroxyl groups, halogen, haloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkyl, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkyl substitutedwith —NR¹⁴R¹⁵, C₁₋₄alkyl substituted with —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkoxy,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂-haloC₁₋₄alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkylsubstituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with—NH—S(═O)₂—C₁₋₄alkyl, C₁₋₄alkyl substituted with—NH—S(═O)₂-haloC₁₋₄alkyl, C₁₋₄alkyl substituted with —NH—S(═O)₂—NR¹⁴R¹⁵,R¹³, —C(═O)—R¹³, C₁₋₄alkyl substituted with R¹³, phenyl optionallysubstituted with R¹⁶, phenylC₁₋₆alkyl wherein the phenyl is optionallysubstituted with R¹⁶, and a 5 or 6-membered aromatic monocyclicheterocyclyl containing at least one heteroatom selected from N, O and Swherein said heterocyclyl is optionally substituted with R¹⁶; or whentwo of the substituents of R⁹ are attached to the same atom, they areoptionally taken together to form a 4 to 7-membered saturated monocyclicheterocyclyl containing at least one heteroatom selected from N, O andS; R¹⁰ and R¹¹ are each independently hydrogen, carboxyl, C₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —C(═O)—NR¹⁴R¹⁵, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl is optionally substituted with one or two hydroxyl groups, R⁶,C₁₋₆alkyl substituted with R⁶, —C(═O)—R⁶, —C(═O)—C₁₋₆alkyl,—C(═O)-hydroxyC₁₋₆alkyl, —C(═O)-haloC₁₋₆alkyl,—C(═O)-hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with —Si(CH₃)₃,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁴R¹⁵; R¹² is hydrogen or C₁₋₄alkyl optionallysubstituted with C₁₋₄alkoxy; R¹³ is C₃₋₈cycloalkyl or a saturated 4 to6-membered monocyclic heterocyclyl containing at least one heteroatomselected from N, O and S, wherein said C₃₋₈cycloalkyl or monocyclicheterocyclyl is optionally substituted with 1, 2 or 3 substituents eachindependently selected from halogen, hydroxyl, C₁₋₆alkyl,—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxy, and —NR¹⁴R¹⁵; R¹⁴ and R¹⁵ are eachindependently hydrogen, or haloC₁₋₄alkyl, or C₁₋₄alkyl optionallysubstituted with a substituent selected from hydroxyl, C₁₋₄alkoxy, aminoand mono- or di(C₁₋₄alkyl)amino; and R¹⁶ is hydroxyl, halogen, cyano,C₁₋₄alkyl, C₁₋₄alkoxy, —NR¹⁴R¹⁵ or —C(═O)NR¹⁴R¹⁵; or an N-oxide thereof,a pharmaceutically acceptable salt thereof or a solvate thereof.
 19. Amethod according to claim 18, wherein the cancer is selected frommultiple myeloma, myeloproliferative disorders, endometrial cancer,prostate cancer, bladder cancer, lung cancer, ovarian cancer, breastcancer, gastric cancer, colorectal cancer, and oral squamous cellcarcinoma.
 20. A method according to claim 18, wherein the cancer isselected from lung cancer, squamous cell carcinoma, liver cancer, kidneycancer, breast cancer, colon cancer, colorectal cancer, and prostatecancer.
 21. A method according to claim 19, wherein the cancer ismultiple myeloma.
 22. A method according to claim 21, wherein the canceris t(4;14) translocation positive multiple myeloma.
 23. A methodaccording to claim 19, wherein the cancer is bladder cancer.
 24. Amethod according to claim 23, wherein the cancer is bladder cancer witha FGFR3 chromosomal translocation.
 25. A method according to claim 23,wherein the cancer is bladder cancer with a FGFR3 point mutation.
 26. Amethod according to claim 18, wherein the cancer is a tumor with amutant of FGFR1, FGFR2, FGFR3 or FGFR4.
 27. A method according to claim18, wherein the cancer is a tumor with a gain-of-function mutant ofFGFR2 or FGFR3.
 28. A method according to claim 18, wherein the canceris a tumor with over-expression of FGFR1.
 29. A method according toclaim 18, wherein the cancer is urothelial carcinoma.
 30. A methodaccording to claim 18, wherein the compound isN-(3,5-dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine;or an N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.
 31. A method according to claim 30, wherein thecompound isN-(3,5-dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine.32. A method according to claim 18, wherein the compound is selectedfrom:N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-N′-(2,2,2-trifluoroethyl)propane-1,3-diamine;andN-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine;or an N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.
 33. A method for treating a subject suffering from, orbeing at risk of suffering from a carcinoma, wherein the carcinoma isselected from a carcinoma of the bladder, breast, colon, kidney,epidermis, liver, lung, oesophagus, head and neck, gall bladder, ovary,pancreas, stomach, gastrointestinal (also known as gastric) cancer,cervix, endometrium, thyroid, prostate, or skin, a hematopoietic tumourof lymphoid lineage; a hematopoietic tumour of myeloid lineage; multiplemyeloma; thyroid follicular cancer; a tumour of mesenchymal origin; atumour of the central or peripheral nervous system; melanoma; seminoma;teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma;or Kaposi's sarcoma, said method comprising administering to the subjecta compound selected from the group consisting of a compound of formula(I)

a tautomeric form, stereochemically isomeric form and isotopic formthereof, wherein n is an integer equal to 0, 1, 2, 3 or 4; R¹ ishydrogen, C₁₋₆alkyl, C₂₋₄alkenyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl is optionally substituted with one or two hydroxyl groups,C₁₋₆alkyl substituted with —NR⁴R⁵, C₁₋₆alkyl substituted with—C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkylsubstituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶,C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkyl substituted with—P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; eachR^(1a) is independently selected from hydrogen, C₁₋₄alkyl,hydroxyC₁₋₄alkyl, C₁₋₄alkyl substituted with amino or mono- ordi(C₁₋₄alkyl)amino or —NH(C₃₋₈cycloalkyl), cyanoC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more fluoroatoms; each R² is independently selected from hydroxyl, halogen, cyano,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, hydroxyhaloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, haloC₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl is optionally substitutedwith one or two hydroxyl groups, hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl, R¹³,C₁₋₄alkyl substituted with R¹³, C₁₋₄alkyl substituted with —C(═O)—R¹³,C₁₋₄alkoxy substituted with R¹³, C₁₋₄alkoxy substituted with —C(═O)—R¹³,—C(═O)—R¹³, C₁₋₄alkyl substituted with —NR⁷R⁸, C₁₋₄alkyl substitutedwith —C(═O)—NR⁷R⁸, C₁₋₄alkoxy substituted with —NR⁷R⁸, C₁₋₄alkoxysubstituted with —C(═O)—NR⁷R⁸, —NR⁷R⁸ and —C(═O)—NR⁷R⁸; or when two R²groups are attached to adjacent carbon atoms they are optionally takentogether to form a radical of formula: —O—(C(R¹⁷)₂)_(p)—O—; —X—CH═CH—;or —X—CH═N—; wherein R¹⁷ is hydrogen or fluorine, p is 1 or 2 and X is Oor S; R³ is hydroxyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxysubstituted with —NR¹¹R¹¹, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,haloC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl, hydroxyhaloC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with carboxyl, C₁₋₆alkylsubstituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl isoptionally substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynylsubstituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted withhydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogensand —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; R⁴ and R⁵ are eachindependently hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl isoptionally substituted with one or two hydroxyl groups,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵, R¹³ or C₁₋₆alkyl substituted with R¹³; R⁶ isC₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to 7-membered monocyclicheterocyclyl containing at least one heteroatom selected from N, O andS; said C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to 7-memberedmonocyclic heterocyclyl, each optionally and each independentlysubstituted by 1, 2, 3, 4 or 5 substituents, each substituentindependently selected from cyano, C₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyl,carboxyl, hydroxyC₁₋₆alkyl, halogen, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl,C₁₋₆alkyl-O—C(═O)—, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —C(═O)—NR¹⁴R¹⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl and C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵; R⁷ and R⁸ are each independently hydrogen,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl orC₁₋₆alkoxyC₁₋₆alkyl; R⁹ is C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl,naphthyl, or 3 to 12 membered monocyclic or bicyclic heterocyclylcontaining at least one heteroatom selected from N, O and S, saidC₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, naphthyl, or 3 to 12 memberedmonocyclic or bicyclic heterocyclyl each optionally and eachindependently substituted with 1, 2, 3, 4 or 5 substituents, eachsubstituent independently selected from ═O, C₁₋₄alkyl, hydroxyl,carboxyl, hydroxyC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, C₁₋₄alkyl-O—C(═O)—,C₁₋₄alkyl substituted with C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkyl-C(═O)—,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl is optionally substitutedwith one or two hydroxyl groups, halogen, haloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkyl, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkyl substitutedwith —NR¹⁴R¹⁵, C₁₋₄alkyl substituted with —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkoxy,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂-haloC₁₋₄alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkylsubstituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with—NH—S(═O)₂—C₁₋₄alkyl, C₁₋₄alkyl substituted with—NH—S(═O)₂-haloC₁₋₄alkyl, C₁₋₄alkyl substituted with —NH—S(═O)₂—NR¹⁴R¹⁵,R¹³, —C(═O)—R¹³, C₁₋₄alkyl substituted with R¹³, phenyl optionallysubstituted with R¹⁶, phenylC₁₋₆alkyl wherein the phenyl is optionallysubstituted with R¹⁶, and a 5 or 6-membered aromatic monocyclicheterocyclyl containing at least one heteroatom selected from N, O and Swherein said heterocyclyl is optionally substituted with R¹⁶; or whentwo of the substituents of R⁹ are attached to the same atom, they areoptionally taken together to form a 4 to 7-membered saturated monocyclicheterocyclyl containing at least one heteroatom selected from N, O andS; R¹⁰ and R¹¹ are each independently hydrogen, carboxyl, C₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —C(═O)—NR¹⁴R¹⁵, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl is optionally substituted with one or two hydroxyl groups, R⁶,C₁₋₆alkyl substituted with R⁶, —C(═O)—R⁶, —C(═O)—C₁₋₆alkyl,—C(═O)-hydroxyC₁₋₆alkyl, —C(═O)-haloC₁₋₆alkyl,—C(═O)-hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with —Si(CH₃)₃,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁴R¹⁵; R¹² is hydrogen or C₁₋₄alkyl optionallysubstituted with C₁₋₄alkoxy; R¹³ is C₃₋₈cycloalkyl or a saturated 4 to6-membered monocyclic heterocyclyl containing at least one heteroatomselected from N, O and S, wherein said C₃₋₈cycloalkyl or monocyclicheterocyclyl is optionally substituted with 1, 2 or 3 substituents eachindependently selected from halogen, hydroxyl, C₁₋₆alkyl,—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxy, and —NR¹⁴R¹⁵; R¹⁴ and R¹⁵ are eachindependently hydrogen, or haloC₁₋₄alkyl, or C₁₋₄alkyl optionallysubstituted with a substituent selected from hydroxyl, C₁₋₄alkoxy, aminoand mono- or di(C₁₋₄alkyl)amino; and R¹⁶ is hydroxyl, halogen, cyano,C₁₋₄alkyl, C₁₋₄alkoxy, —NR¹⁴R¹⁵ or —C(═O)NR¹⁴R¹⁵; or an N-oxide thereof,a pharmaceutically acceptable salt thereof or a solvate thereof.
 34. Amethod according to claim 33, wherein the carcinoma is glioblastomamultiforme.
 35. A method according to claim 33, wherein the compound isN-(3,5-dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine;or an N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.
 36. A method according to claim 35, wherein thecompound isN-(3,5-dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine.37. A method of inhibiting a FGFR kinase, which method comprisescontacting the kinase with a kinase-inhibiting compound selected fromthe group consisting of a compound of formula (I)

a tautomeric form, stereochemically isomeric form and isotopic formthereof, wherein n is an integer equal to 0, 1, 2, 3 or 4; R¹ ishydrogen, C₁₋₆alkyl, C₂₋₄alkenyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl is optionally substituted with one or two hydroxyl groups,C₁₋₆alkyl substituted with —NR⁴R⁵, C₁₋₆alkyl substituted with—C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkylsubstituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶,C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkyl substituted with—P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; eachR^(1a) is independently selected from hydrogen, C₁₋₄alkyl,hydroxyC₁₋₄alkyl, C₁₋₄alkyl substituted with amino or mono- ordi(C₁₋₄alkyl)amino or —NH(C₃₋₈cycloalkyl), cyanoC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more fluoroatoms; each R² is independently selected from hydroxyl, halogen, cyano,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, hydroxyhaloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, haloC₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl is optionally substitutedwith one or two hydroxyl groups, hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl, R¹³,C₁₋₄alkyl substituted with R¹³, C₁₋₄alkyl substituted with —C(═O)—R¹³,C₁₋₄alkoxy substituted with R¹³, C₁₋₄alkoxy substituted with —C(═O)—R¹³,—C(═O)—R¹³, C₁₋₄alkyl substituted with —NR⁷R⁸, C₁₋₄alkyl substitutedwith —C(═O)—NR⁷R⁸, C₁₋₄alkoxy substituted with —NR⁷R⁸, C₁₋₄alkoxysubstituted with —C(═O)—NR⁷R⁸, —NR⁷R⁸ and —C(═O)—NR⁷R⁸; or when two R²groups are attached to adjacent carbon atoms they are optionally takentogether to form a radical of formula: —O—(C(R¹⁷)₂)_(p)—O—; —X—CH═CH—;or —X—CH═N—; wherein R¹⁷ is hydrogen or fluorine, p is 1 or 2 and X is Oor S; R³ is hydroxyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxysubstituted with —NR¹⁰R¹¹, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,haloC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl, hydroxyhaloC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with carboxyl, C₁₋₆alkylsubstituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl isoptionally substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynylsubstituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted withhydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogensand —NR¹⁰R¹¹, C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; R⁴ and R⁵ are eachindependently hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl isoptionally substituted with one or two hydroxyl groups,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵, R¹³ or C₁₋₆alkyl substituted with R¹³; R⁶ isC₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to 7-membered monocyclicheterocyclyl containing at least one heteroatom selected from N, O andS; said C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to 7-memberedmonocyclic heterocyclyl, each optionally and each independentlysubstituted by 1, 2, 3, 4 or 5 substituents, each substituentindependently selected from cyano, C₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyl,carboxyl, hydroxyC₁₋₆alkyl, halogen, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl,C₁₋₆alkyl-O—C(═O)—, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —C(═O)—NR¹⁴R¹⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl and C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵; R⁷ and R⁸ are each independently hydrogen,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl orC₁₋₆alkoxyC₁₋₆alkyl; R⁹ is C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl,naphthyl, or 3 to 12 membered monocyclic or bicyclic heterocyclylcontaining at least one heteroatom selected from N, O and S, saidC₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, naphthyl, or 3 to 12 memberedmonocyclic or bicyclic heterocyclyl each optionally and eachindependently substituted with 1, 2, 3, 4 or 5 substituents, eachsubstituent independently selected from ═O, C₁₋₄alkyl, hydroxyl,carboxyl, hydroxyC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, C₁₋₄alkyl-O—C(═O)—,C₁₋₄alkyl substituted with C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkyl-C(═O)—,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl is optionally substitutedwith one or two hydroxyl groups, halogen, haloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkyl, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkyl substitutedwith —NR¹⁴R¹⁵C₁₋₄alkyl substituted with —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkoxy,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂-haloC₁₋₄alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkylsubstituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with—NH—S(═O)₂—C₁₋₄alkyl, C₁₋₄alkyl substituted with—NH—S(═O)₂-haloC₁₋₄alkyl, C₁₋₄alkyl substituted with —NH—S(═O)₂—NR¹⁴R¹⁵,R¹³, —C(═O)—R¹³, C₁₋₄alkyl substituted with R¹³, phenyl optionallysubstituted with R¹⁶, phenylC₁₋₆alkyl wherein the phenyl is optionallysubstituted with R¹⁶, and a 5 or 6-membered aromatic monocyclicheterocyclyl containing at least one heteroatom selected from N, O and Swherein said heterocyclyl is optionally substituted with R¹⁶; or whentwo of the substituents of R⁹ are attached to the same atom, they areoptionally taken together to form a 4 to 7-membered saturated monocyclicheterocyclyl containing at least one heteroatom selected from N, O andS; R¹⁰ and R¹¹ are each independently hydrogen, carboxyl, C₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —C(═O)—NR¹⁴R¹⁵, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl is optionally substituted with one or two hydroxyl groups, R⁶,C₁₋₆alkyl substituted with R⁶, —C(═O)—R⁶, —C(═O)—C₁₋₆alkyl,—C(═O)-hydroxyC₁₋₆alkyl, —C(═O)-haloC₁₋₆alkyl,—C(═O)-hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with —Si(CH₃)₃,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁴R¹⁵; R¹² is hydrogen or C₁₋₄alkyl optionallysubstituted with C₁₋₄alkoxy; R¹³ is C₃₋₈cycloalkyl or a saturated 4 to6-membered monocyclic heterocyclyl containing at least one heteroatomselected from N, O and S, wherein said C₃₋₈cycloalkyl or monocyclicheterocyclyl is optionally substituted with 1, 2 or 3 substituents eachindependently selected from halogen, hydroxyl, C₁₋₆alkyl,—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxy, and —NR¹⁴R¹⁵; R¹⁴ and R¹⁵ are eachindependently hydrogen, or haloC₁₋₄alkyl, or C₁₋₄alkyl optionallysubstituted with a substituent selected from hydroxyl, C₁₋₄alkoxy, aminoand mono- or di(C₁₋₄alkyl)amino; and R¹⁶ is hydroxyl, halogen, cyano,C₁₋₄alkyl, C₁₋₄alkoxy, —NR¹⁴R¹⁵ or —C(═O)NR¹⁴R¹⁵; or an N-oxide thereof,a pharmaceutically acceptable salt thereof or a solvate thereof.
 38. Amethod according to claim 37, wherein the compound isN-(3,5-dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine;or an N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.
 39. A method according to claim 38, wherein thecompound isN-(3,5-dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine.40. A method according to claim 1, further comprising administering tothe subject one or more other anticancer agents.
 41. A method accordingto claim 40, wherein the one or more other anticancer agents comprises akinase inhibitor.
 42. A method according to claim 40, wherein thecompound isN-(3,5-dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine;or an N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.
 43. A method according to claim 42, wherein thecompound isN-(3,5-dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine.44. A process for the preparation of a compound selected from the groupconsisting of a compound of formula (I), a tautomeric form,stereochemically isomeric form and isotopic form thereof, or an N-oxide,a pharmaceutically acceptable salt, or a solvate of the compound, saidprocess comprising: (i) deprotecting a compound of formula (XXX) whereinP represents a suitable protective group, in the presence of a suitableacid,

(ii) the reaction of a compound of the formula (IX) or (IX′):

or a protected form thereof, with an appropriately substituted amine ora reactive derivative thereof, in the presence of a suitable base,and/or in the presence or absence of a solvent; or (iii) the reaction ofa compound of the formula (VI):

or a protected form thereof, with a compound of formulaW₆—C₁₋₆alkyl-NR¹⁰P wherein P represents a suitable protective group andW₆ represents a suitable leaving group, in the presence of a suitablebase, and a suitable solvent, followed by removing P and optionallyremoving any further protecting group present; or (iv) the reaction of acompound of the formula (VI):

or a protected form thereof, with a compound of formulaW₆—C₁₋₆alkyl-NHR¹⁰ wherein W₆ represents a suitable leaving group, inthe presence of a suitable base, and a suitable solvent; (v) thereaction of a compound of formula (XXXVI)

with hydrazine in the presence of a suitable solvent; or (vi) thereaction of a compound of formula (IX-1) wherein R^(u) represents—O—S(═O)₂—CH₃,

with an intermediate of formula (X) in the presence of a suitablesolvent; or (vii) the reaction of a compound of formula (VI)

with an intermediate of formula W₁₁—R^(3b) wherein R^(3b) representsoptionally substituted C₂₋₆alkynyl and W₁₁ represents a suitable leavinggroup, in the presence of a suitable base and a suitable solvent; or(viii) the reaction of a compound of formula (VIII′) wherein R^(x) andR^(y) represent C₁₋₄alkyl, and R^(z) represents C₁₋₄alkyl or phenyl,

with a suitable acid, in the presence of a suitable solvent; or (viii)deprotecting a compound of formula (XXXXII)

in the presence of a suitable base and a suitable solvent; or (ix) thereaction of a compound of formula (VI)

with di(C₁₋₆alkyl)vinylphosphonate in the presence of a suitablecatalyst and a suitable solvent; or (x) deprotecting a compound offormula (XXXXI) wherein P represents a suitable protective group

in the presence of a suitable base and a suitable solvent; or (xi) thereaction of a compound of formula (XIX) wherein R^(3a) representsoptionally substituted C₁₋₆alkyl, with a compound of formula (III)

in the presence of a suitable catalyst, a suitable ligand, a suitablebase, and a suitable solvent; or (xii) the reaction of a compound offormula (XX) wherein R^(3a) represents optionally substituted C₁₋₆alkyl,with a compound of formula (XIV) wherein W₅ represents a suitableleaving group

in the presence of a suitable catalyst, a suitable ligand, a suitablebase, and a suitable solvent; or (xiii) the reaction of a compound offormula (XXXI)

with W₈—CN, wherein W₈ represents a suitable leaving group, in thepresence of a suitable base and a suitable solvent; or (xiv) thereaction of a compound of formula (XXXV)

with a suitable base in the presence of a suitable solvent; or (xv)deprotecting a compound of formula (XXVI) wherein P represents asuitable protective group,

in the presence of a suitable acid, or a suitable de-silylating agent,and a suitable solvent; or (xvi) the reaction of a compound of formula(XXIX) with a compound of formula (XXI)

in the presence of suitable peptide coupling reagents; or (xvii) thereaction of a compound of formula (XXIX)

with NHR⁴R⁵ in the presence of suitable peptide coupling reagents and asuitable base, and a suitable solvent; or (xviii) reacting the belowcompound

with NHR⁷R⁸ in the presence of a suitable base and a suitable solvent;or (xviii) deprotecting the below compound

in the presence of hydrazine monohydrate and a suitable solvent; whereinn is an integer equal to 0, 1, 2, 3 or 4; R¹ is hydrogen, C₁₋₆alkyl,C₂₋₄alkenyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,cyanoC₁₋₄alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl is optionallysubstituted with one or two hydroxyl groups, C₁₋₆alkyl substituted with—NR⁴R⁵, C₁₋₆alkyl substituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkylsubstituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶,C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkyl substituted with—P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; eachR^(1a) is independently selected from hydrogen, C₁₋₄alkyl,hydroxyC₁₋₄alkyl, C₁₋₄alkyl substituted with amino or mono- ordi(C₁₋₄alkyl)amino or —NH(C₃₋₈cycloalkyl), cyanoC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more fluoroatoms; each R² is independently selected from hydroxyl, halogen, cyano,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, hydroxyhaloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, haloC₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl is optionally substitutedwith one or two hydroxyl groups, hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl, R¹³,C₁₋₄alkyl substituted with R¹³, C₁₋₄alkyl substituted with —C(═O)—R¹³,C₁₋₄alkoxy substituted with R¹³, C₁₋₄alkoxy substituted with —C(═O)—R¹³,—C(═O)—R¹³, C₁₋₄alkyl substituted with —NR⁷R⁸, C₁₋₄alkyl substitutedwith —C(═O)—NR⁷R⁸, C₁₋₄alkoxy substituted with —NR⁷R⁸, C₁₋₄alkoxysubstituted with —C(═O)—NR⁷R⁸, —NR⁷R⁸ and —C(═O)—NR⁷R⁸; or when two R²groups are attached to adjacent carbon atoms they are optionally takentogether to form a radical of formula: —O—(C(R¹⁷)₂)_(p)—O—; —X—CH═CH—;or —X—CH═N—; wherein R¹⁷ is hydrogen or fluorine, p is 1 or 2 and X is Oor S; R³ is hydroxyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxysubstituted with —NR¹⁰R¹¹, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,haloC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl, hydroxyhaloC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with carboxyl, C₁₋₆alkylsubstituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl isoptionally substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynylsubstituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted withhydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogensand —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; R⁴ and R⁵ are eachindependently hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl isoptionally substituted with one or two hydroxyl groups,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵, R¹³ or C₁₋₆alkyl substituted with R¹³; R⁶ isC₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to 7-membered monocyclicheterocyclyl containing at least one heteroatom selected from N, O andS; said C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to 7-memberedmonocyclic heterocyclyl, each optionally and each independentlysubstituted by 1, 2, 3, 4 or 5 substituents, each substituentindependently selected from cyano, C₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyl,carboxyl, hydroxyC₁₋₆alkyl, halogen, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl,C₁₋₆alkyl-O—C(═O)—, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —C(═O)—NR¹⁴R¹⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl and C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵; R⁷ and R⁸ are each independently hydrogen,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl orC₁₋₆alkoxyC₁₋₆alkyl; R⁹ is C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl,naphthyl, or 3 to 12 membered monocyclic or bicyclic heterocyclylcontaining at least one heteroatom selected from N, O and S, saidC₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, naphthyl, or 3 to 12 memberedmonocyclic or bicyclic heterocyclyl each optionally and eachindependently substituted with 1, 2, 3, 4 or 5 substituents, eachsubstituent independently selected from ═O, C₁₋₄alkyl, hydroxyl,carboxyl, hydroxyC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, C₁₋₄alkyl-O—C(═O)—,C₁₋₄alkyl substituted with C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkyl-C(═O)—,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl is optionally substitutedwith one or two hydroxyl groups, halogen, haloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkyl, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkyl substitutedwith —NR¹⁴R¹⁵, C₁₋₄alkyl substituted with —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkoxy,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂-haloC₁₋₄alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkylsubstituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with—NH—S(═O)₂—C₁₋₄alkyl, C₁₋₄alkyl substituted with—NH—S(═O)₂-haloC₁₋₄alkyl, C₁₋₄alkyl substituted with —NH—S(═O)₂—NR¹⁴R¹⁵,R¹³, —C(═O)—R¹³C₁₋₄alkyl substituted with R¹³, phenyl optionallysubstituted with R¹⁶, phenylC₁₋₆alkyl wherein the phenyl is optionallysubstituted with R¹⁶, and a 5 or 6-membered aromatic monocyclicheterocyclyl containing at least one heteroatom selected from N, O and Swherein said heterocyclyl is optionally substituted with R¹⁶; or whentwo of the substituents of R⁹ are attached to the same atom, they areoptionally taken together to form a 4 to 7-membered saturated monocyclicheterocyclyl containing at least one heteroatom selected from N, O andS; R¹⁰ and R¹¹ are each independently hydrogen, carboxyl, C₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —C(═O)—NR¹⁴R¹⁵, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl is optionally substituted with one or two hydroxyl groups, R⁶,C₁₋₆alkyl substituted with R⁶, —C(═O)—R⁶, —C(═O)—C₁₋₆alkyl,—C(═O)-hydroxyC₁₋₆alkyl, —C(═O)-haloC₁₋₆alkyl,—C(═O)-hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with —Si(CH₃)₃,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵; R¹² is hydrogen or C₁₋₄alkyl optionally substitutedwith C₁₋₄alkoxy; R¹³ is C₃₋₈cycloalkyl or a saturated 4 to 6-memberedmonocyclic heterocyclyl containing at least one heteroatom selected fromN, O and S, wherein said C₃₋₈cycloalkyl or monocyclic heterocyclyl isoptionally substituted with 1, 2 or 3 substituents each independentlyselected from halogen, hydroxyl, C₁₋₆alkyl, —C(═O)—C₁₋₆alkyl,C₁₋₆alkoxy, and —NR¹⁴R¹⁵; R¹⁴ and R¹⁵ are each independently hydrogen,or haloC₁₋₄alkyl, or C₁₋₄alkyl optionally substituted with a substituentselected from hydroxyl, C₁₋₄alkoxy, amino and mono- ordi(C₁₋₄alkyl)amino; and R¹⁶ is hydroxyl, halogen, cyano, C₁₋₄alkyl,C₁₋₄alkoxy, —NR¹⁴R¹⁵ or —C(═O)NR¹⁴R¹⁵; and optionally thereafterconverting one compound selected from the group consisting of a compoundof formula (I), a tautomeric form, stereochemically isomeric form andisotopic form thereof into another compound selected from the groupconsisting of a compound of formula (I), a tautomeric form,stereochemically isomeric form and isotopic form thereof.
 45. A processaccording to claim 44, said process comprising: (ii) the reaction of acompound of the formula (IX) or (IX′):

or a protected form thereof, with an appropriately substituted amine ora reactive derivative thereof, selected from NHR¹⁰R¹¹ (X), NHR¹⁰P(X-a),and a suitable nitrogen containing ring within the definition of R⁹:H-

(XXI), optionally in a sealed vessel, in the presence of a suitablebase, and/or in the presence or absence of a solvent.